5,10-epoxy-5h-dibenzo(a,d)cycloheptenes and related compounds



United States Patent 3,494,935 5,10-EPOXY-5H-DIBENZO[a,d1CYCLOI-IEPTENES AND RELATED COMPOUNDS Marcia E. Christy, Box 31511, RR. 2,

Perkasie, Pa. 18944 No Drawing. Continuation-impart of application Ser. No.

286,962, June 11, 1963. This application Aug. 23, 1965, Ser. No. 481,908

Int. Cl. C07d 7/10, 5/10; 'C07c 13/54 U.S. C]. 260-327 88 Claims This application is a continuation-in-part of copending application Ser. No. 306,639, filed Sept. 4, 1963, now abandoned, which is, in turn, a continuation-in-part of application Ser. No. 286,962, filed June 11, 1963, now abandoned.

This invention relates to derivatives of dibenzocycloheptenes. In particular, the invention relates to 10,1l-dihydro-5 3-substituted-aminopropyl -5 1 O-epoxy-S H dibenzo-[a,d] cycloheptenes, 10,1 l-dihyd'ro-5-( 3-substitutedaminopropyl)-5,10-epoxy ll substituted-SH-dibenzo [a,d]cycloheptenes, and methods of preparing the same. The invention also relates to intermediates useful in the preparation of the above compounds as well as processes for the preparation of said intermediates.

The end compounds embraced within the scope of the present invention may be represented by the following structural formulae wherein Z is a radical selected from the group consisting of H, OH, OY, =NOR, =NOY, NH NHSO R,

=NNH when Z is OH or OY, there can be an alkyl group as defined by R'" replacing the hydrogen at the 11 position; R is lower alkyl, straight or branched chain, preferably having up to 6 carbon atoms,

wherein B is hydrogen, halogen, trifluoromethyl, lower alkyl, straight or branched chain, preferably having up to 4 carbon atoms, lower alkoxy, straight or branched chain, preferably having up to 4 carbon atoms, and n represents a whole number of from 0 to 3; R is hydrogen or lower alkyl, straight or branched chain, preferably having up to 6 carbon atoms; R is lower alkyl, straight or branched chain, preferably having up to 6 carbon atoms; R" is lower alkyl, straight or branched chain, preferably having up to 6 carbon atoms; R is lower alkyl, straight or branched chain, preferably having up to 6 carbon atoms; Y is alkanoyl, straight or branched chain, preferably having up to 18 carbon atoms and may contain unsaturation,

wherein B and n are as defined above; and X and X', which may be similar or dissimilar, are hydrogen, an alkyl group having up to 6 carbon atoms, and alkenyl lot:

group having up to 6 carbon atoms, halogen, trifluoromethyl, hydroxyl, an alkoxy group having up to 4 carbon atoms, mercapto, an alkylmercapto group having up to 4 carbon atoms, an alkylsulfonyl group having up to 4 carbon atoms, sulfamoyl, an alkylsulfamoyl group having up to 4 carbon atoms, or a dialkylsulfamoyl group having up to 8 carbon atoms. More than one of these substituents may be on each of the benzenoid rings.

The radicals R and R" may be similar or dissimilar and they may be linked together through an atom of carbon, nitrogen or oxygen to form a heterocyclic ring having from 5 to 6 atoms therein such as l-piperidyl, lpyrrolidyl, 4-morpholinyl and 1-loweralkyl-4-piperazinyl, the lower alkyl substituent of the latter preferably having up to 4 carbon atoms.

The compounds represented by the above structural formulae may also have substituents on the propyl side chain such as lower alkyl radicals, preferably having from 1 to 4 carbon atoms.

Representative end compounds encompassed within the scope of the present invention include:

10,1 l-dihydro-5,l0-epoxy-1 1-hydroXy5-[3-( 1-piperidy1)- propyl] -5H-dibenzo [a,d] cycloheptene 10,1 l-dihydro-S,l0-epoXy-1 1-hydroxy-5-[3-( 1-methyl-4- piperazinyl) -propyl] -5H-dibenzo [a,d] cycloheptene 10,1l-dihydro-5,10epoxy-l l-hydroxy-S- 3-dimethylarninopropyl -5 H-dibenzo a,d] cycloheptene 10,1 l-dihydro-5,10-epoXy-1 l-hydroxy-S- 3-methylaminopropyl) -5H-dibenzo [a,d1cycloheptene 7-chloro-10, l 1-dihydro-5,10epoXy-1 l-hydroxy-S- 3- dimethylaminopropyl -5H-dibenzo [a,d] cycloheptene 10,1 1-di-hydro-5-(3-dimethylaminopropyl)-5,10-epoxy-1lhydroxyimino-3-methylsulfonyl-5 H-dib enzo [a,d] cycloheptene 1 l-methylaminol 0,1 1-dihydr0-5-( 3-dimethylaminopropyl) -5, l O-epoxy-SH-dibenzo [a,d] cycloheptene 1l-diethylamino-10,1 l-dihydro-S- 3-dimethylaminopropyl)-5,10-epoXy-5H-dibenzo[a,d1cycloheptene 1 0,1l-dihydro-S-(3-dimethylaminopropyl)-5, 10-epoXy-l lethyl-l l-hydroxy-SH-dibenzo [a,d] cycloheptene 10,1 1-dihydro-5,l0-epoXy-l l-hydroxy-S- 3-methylaminopropyl) -3-methylsulfonyl-5H-dibenzo[a,d]

cycloheptene 10,1 l-dihydro-S, 1 O-epoxy-l 1-hydroxy-5- 3-dimethylaminopropyl)-3-trifluoromethyl-5H-dibenzo[a,d]

cycloheptene 10,1 1-dihydro-5,10-epoxy-1 l-hydroxy-5-( 3-diethylaminopropyl) -3-dimethylsulfamoyl-5H-dibenzo [a,d]

cycloheptene 10,1 l-dihydro-S, lO-epoxy-S- 3-dimethylaminopropyl) SH-dibenzo-[a,dJcycloheptene 10,1 1-dihydro-5,10-epoxy-S-(3-methylaminopropyl)-5H- dibenzo- [a,d] cycloheptene 1 0,1 l-dihydro-S,10-epoxy-5-(3-methylaminopropyl)-3- methylsulfonyl-S H-dib enzo [a,d] cycloheptene 10,1l-dihydro-5,10-epoxy-5-(3-dimethylarninopropyl)-3- trifluoromethyl-SH-dibenzo [a,d] cycloheptene 10, 1 l-dihydro-5,10-epoXy-5- 3-diethylaminopropyl) 3- dimethylsulfamoyl-SH-dibenzo [a,d] cycloheptene 1l-acetoxy-10,ll-dihydro-S,10-epoxy-5-(3-methylaminocycloheptene 11-benZoyloxy-l0,l l-dihydro-S,10-epoxy-5-(3-methylaminopropyl) -5H-dibenzo [a,d] cycloheptene 1 1-p-chlorobenzoyloxy-10,1 l-dihydro-S- 3-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo[a,d]

cycloheptene 10,11-dihydro--(3 -dimethylaminopropylj-5,10-epoxy1 1- p-methoxybenzoyloxy-SH-dibenzo [a,d] cycloheptene 10,1 1-dihydro-5- 3 -dimethylaminopropyl(-5,10-epoxy-11- m-trifluoromethylbenzoyloxy-SH-dibenzo [a,d] cycloheptene 10,ll-dihydro-S,10-epoxy-5-(3-methylaminopropyl)-11- phenylacetoxy-SH-dibenzo a,d] cycloheptene 10,1l-dihydro-S-(3-dimethylaminopropyl)-5,l0-epoxy-ll hydrocinnamoyloxy-SH-dibenzo a,d] cycloheptene 10,1l-dihydro-S,10-epoxy-5-(3-methylaminopropyl)-1lpropionyloxy-SH-dibenzo [a,d] cycloheptene 1 1-acet0xyimino-10,1 1-dihydro-5-( 3-dimethylaminopropyl)-3-dimethylsulfamoyl-5,10-epoXy-5H- dibenzo a,d] cycloheptene 1 1-benzoyloxyimino-10,1l-dihydro-S,10-epoxy-5-(3- methylaminopropyl -5H-dibenzo [a,d] cycloheptene 10,1 l-dihydro-5-(3-dimethylaminopropyl)-5,10epoXy- 1l-phenylacetoxyimino-SH-dibenzo a,d] cycloheptene 1l-p-chlorobenzoyloxyimino-10,1 l-dihydro-S- 3 -dimethylaminopropyl -5 -e poxy-SH-dibenzo [a,d] cycloheptene 10,1l-dihydro-S-(3-dimethylaminopropyl)-5,10-epoXy-l1- p-tolyloxyimino-5H-dibenzo [a,d] cycloheptene 10,1l-dihydro-5-(3 -dimethylaminopropyl)-5,l0-epoxy-1lphenylacetoxyimino-SH-dibenzo [a,d] cycloheptene 10,11-dihydro-5-(3-dimethylaminopropyl-5,IO-epoxy-l1- hydrocinnamoyloxyimino-5H-dibenzo [a,d cycloheptene 10,1l-dihydro-S-(S-dimethylaminopropyl)-5,10-ep0xy-1 1- propoxyimino-SH-dibenzo [a,d] cycloheptene 1l-benzenesulfonamido-10,1 1-dihydr0-5-(3-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo[a,d] cycloheptene 10,1 l-dihydro-S- 3 -dimethylaminopropyl)-5,10'epoxy-11- p-toluenesulfonamido-SH-dib'enzo [a,d] cycloheptene 10,1l-dihydro-S-(3-dimethylaminopropyl)-5,10epoXy-1lphenylmethanesulfonamide-SH-dibenzo [a,d] cycloheptene 10,1 1-dihydro-5-( 3-dirnethylaminopropyl) -5, 1 O-epoxy- 5 H-dibenzo [a,d] cycloheptene-N-oxide 10,11-dihydro-1l-dimethylamino-S,10-epoxy-5-(3-dirnethylaminopropyl -5H-dibenzo [a,d] cycloheptene-N,N- dioxide The compounds represented by the above structural formulae can advantageously be employed in pharmaceutical applications because they have been found to possess anti-depressant activity. As anti-depressants, they may be administered orally in the form of tablets, powders, sustained release pellets and the like or they may be administered orally or parenterally in the form of aqueous solutions or suspensions. When administered orally or parenterally, satisfactory results are obtained at a daily dosage level of from about one mg. to about 300 mgs, preferably given in divided doses over the day or in sustained release form. The compounds are preferably administered in the form of their non-toxic acid addition salts and these salts are included within the scope of this invention. In addition, the compounds represented by structural Formula I may be converted to the N-oxides. These compounds, as well as their acid addition salts, possess antidepressant activity and are also included within the scope of this invention.

The compounds of structural Formula I, wherein Z is hydroxyl and X, X, R and R are as defined, may be prepared by treating a 311,125 dihydro 8H dibenzo [3,4:6,7]-cyclohepta[1,2-d]-1,3-dioxol-8-one with a Grignard reagent, namely, a tertiaryaminopropylmagnesium halide, and the Grignard adduct obtained hydrolyzed to form the corresponding 3a,1Z/i-dihydro-S-hydroxy-S-(3- tertiaryaminopropyl) 8H dibenzoL3,4:6,7]cyclohepta 4 [1,2-d]l,3-dioxole. The latter compound then is hydrolyzed under suitable conditions to effect ring closure and form the corresponding 10,1l-dihydro-5,l0-epoxy-1l-hydroxy-5-(3-tertiaryaminopropyl)-5H dibenzo[a,d]cycloheptene. This process may be illustrated as follows:

In the above process, Hal represents halogen, preferably chlorine or bromine, R and R" are as previously defined and R and R are hydrogen, alkyl, aryl or aralkyl or may be linked together to form a ring having 5 to 8 carbon atoms.

The starting compound, wherein X and X are both hydrogen and R and R are both methyl, namely, the 3a,1ZB-dihydro-2,2-dimethyl-8H dibenzo[3,4:6,7]-cyclohepta[1,2-d]-1,3-dioXol-8-one, may be prepared in the manner described by G. L. Buchanan and D. B. Jhaveri in the J. Org. Chem., 26, 4295-4299 (1961). Those starting compounds, wherein at least one of X and X is other than hydrogen, may be prepared from the corresponding nuclearly substituted SH-dibenzo[a,d]cyclohepten-5-one utilizing the procedure of G. L. Buchanan and D. B. Jhaveri referred to above. The latter compounds may be prepared following the teachings of T. W. Campbell et al. in an article appearing in Helv. Chem. Acta, vol. 36, pp. 14891499 (1953), or as described in the examples.

Those starting compounds, wherein R and R are other than methyl, may be prepared from the corresponding diol by treatment with an appropriate aldehyde or ketone utilizing the procedure described by G. L. Buchanan and D. B. Jhaveri for the preparation of the acetonide of the trans diol appearing in the article referred to above.

It should be noted that inasmuch as the R and R substituents are removed during the preparation of the end compounds of the invention, the selection of the particular starting compound with respect to these substituents will be dependent only upon their ease of preparation and the removal of the R and R substituents during subsequent hydrolysis.

The Grignard reagent employed in Step A of the above process may be prepared by known procedures, but it has been found that it may be prepared in high yields as follows:

RI Mg HalCHaCI-Iz CH2N\ tetrahydroiuran W the solvent for the reaction results in a rapid production of the Grignard reagent in high yield.

The reaction with the Grignard reagent (Step A) is preferably initially carried out at low temperature such as is obtained by the use of an ice-bath and finally may continue at room temperature. It has been found that tetrahydrofuran is a suitable solvent for carrying out the reaction and, accordingly, the ketone may be added directly to the reaction mixture in which the Grignard reagent was prepared. However, any inert solvent for the reactants may be employed.

After the addition reaction is completed, the bulk of the solvent is removed by vacuum distillation, the Grignard adduct dissolved in a suitable solvent such as ben zene, and hydrolyzed by the addition of water or ammonium chloride solution with cooling. The product is recovered by evaporation of the solvent after the removal of any residual inorganic material by decantation or filtration.

Conversion of the carbinol to the corresponding 5,10- epoxy-ll-hydroxy derivative (Step B) is effected by hydrolyzing the former in a suitable solvent, preferably at elevated temperatures, and in the presence of an acidic catalyst such as, for example, p-toluenesulfonic acid, sulfuric acid, trifiuoroacetic acid, hydrochloric acid and the like. A variety of solvents may be utilized, but it is preferred to employ a lower alkanol such as methanol, ethanol, propanol-2 and the like. Where the product is insoluble in the solvent employed, it may be recovered (as the salt) by filtration, and further purified by conventional methods. Where the product is soluble in the solvent employed, it may be recovered (as the base) by evaporation of the solvent, diluting with water, neutralizing any residual acid with sufficient alkali to render the medium basic and col lecting the precipitate which forms by filtration.

The preparation of those compounds represented by structural Formula I, wherein Z is hydrogen and X, X, R and R" are as defined, may be accomplished from the corresponding ll-hydroxy compound obtained in Step B. This process may be illustrated as follows:

O Oxidation X X Step 0 RI CH2CH2CH2N \RII 0 g X X R! CH2CH2CH2N \RII Dithiol Step D HSCH2CH2CH2SH Desulturrzatron O l Raney Nickel Step E CH2OH2CH2N /RI CHzCHzCHzN The conversion of the ll-hydroxy compound to the corresponding ll-keto compound can be efiected employing the standard Oppenauer oxidation reaction. If desired, the product may be isolated in conventional manner. Conversion of the ketone to the corresponding thioketal (Step D) is accomplished by contacting the former with a dithiol such as ethylene dithiol or trimethylene dithiol in the presence of boron trifluoride etherate or zinc chloride-hydrochloric acid and the like. The resulting product which, if desired, can be isolated by conventional methods, is then desulfurized employing Raney nickel in a suitable solvent such as a lower alkanol, preferably ethanol. The product may be recovered by evaporation of the solvent.

The preparation of those compounds represented by structural Formula II, wherein Z is limited to hydrogen, can be readily efiected by dealkylation of the corresponding compound of structural Formula I, wherein R and R" are both lower alkyl, and preferably are the same. This process may be illustrated as follows:

Halolorrnat e Hal 0 O O R Step G CHzCHrCHzNHR' wherein X, X and R are as previously defined and R is alkyl, aralykyl or aryl. It will be readily appreciated by those skilled in the art that inasmuch as the R substituent is removed during the dealkylation, the selection of the particular haloformate will be limited only by its availability and subsequent ease of hydrolysis of the intermediate urethane produced.

The preparation of those compounds of structural Formula II, wherein Z is hydroxy, can be readily accomplished by dealkylating the corresponding ll-hydroxy compound of structural Formula I employing a haloformate as illustrated above. However, if it is desired the hydroxy group may be protected during the reaction with the haloformate. This is readily accomplished by acylatin the starting 5-(3-dialkylaminopropyl)-10,1l-dihydro- 5,10-epoxy-1l-hydroxy 5H dibenzo[a,d]cycloheptene (Step F) employing any of the common acylating agents. The preferred acylating agents are the acid anhydrides, such as acetic anhydride, since they can serve as both solvent and reagent. Once having obtained the acylated derivative, the dealkylation may proceed as indicated by Steps G and H. This process may be illustrated as follows:

(TE 5 \y/ wherein X, X, R, and Y are as previously defined. Insofar as the substituent Y is concerned, the selection thereof is not critical and is dependent only on the stability of the acylating agent and the ease of hydrolysis of the acyl moiety.

Step G of the above-illustrated processes involves the condensation of the tertiary amino compound with a haloforrnate to form the corresponding urethane. While the reaction with the haloformate can be carried out in the absence of a solvent, it is preferable to employ an excess of the haloformate. Other suitable solvents include the aromatic hydrocarbons such as benzene and toluene, aliphatic hydrocarbons such as heptane and hexane, and the halogenated hydrocarbons such as chloroform and carbon tetrachloride. The reaction may be carried out at room temperature, although an elevated temperature is preferred. At the conclusion of the reaction, the urethane intermediate is recovered in conventional manner.

The urethane intermediate thus produced then is subjected to hydrolysis (Step H). The hydrolysis of the urethane is preferably carried out under basic conditions. After completion of the hydrolysis, the desired product is recovered in conventional manner, such as by extraction into a suitable solvent and evaporation of the solvent.

If it is desired, the compounds represented by structural Formula II, wherein Z is hydrogen, also may be prepared by first dealkylating the -(3-dialkylaminopropyl)-10,1l-dihydro-5,1l-epoxy-ll-hydroxy- 5H dibenzo [a,d]cycloheptene or ll-acyloxy derivative thereof, in the manner described in Steps F, G and H above, to form the corresponding S-(3-alkylaminopropyl)-l0,ll-dihydro- 5,10-epoxy-1 l-hydroxy-SH-dibenzo [a,d] cycloheptene and then converting the latter to the correspondin 5-(3- alkylaminopropyl) 10,11 dihydro 5,10 epoxy-SH-dibenzo[a,d]cycloheptene, following the procedure described in Steps C, D and E above.

As noted hereinabove, the acylated compounds that are obtained in Step F as intermediates also possess significant anti-depressant activity. The same is true with respect to the acylated compounds included in structural Formulae I and II hereinabove where R and R are as defined. The ll-acyloxy compounds included in structural Formula I are readily prepared by acylating the corresponding ll-hydroxy compound obtained in Step B in the manner described in Step F hereinabove. The ll-acyloxy compounds included in structural Formula II may also be prepared following the general procedure COOR" epoxy-ll-hydroxy 5 (3-alkylaminopropyl)derivative, preferably a salt derived from a strong acid such as, for example, the hydrochloride.

The preparation of those compounds represented by structural Formula I, wherein Z is a substituted imino radical (:NOR) and R, R, R", X, and X are as defined, may be accomplished by treating the ll-keto compound obtained in Step C with hydroxylamine or an appropriately substituted hydroxylamine. This process may be illustrated as follows:

The conversion of the ll-keto compound to the corresponding ll-hydro'xylimi'no compound is preferably carried out in the presence of a suitable solvent and at elevated temperatures, preferably the reflux temperature of the mixture. Suitable solvents which may be employed are the lower alkanols and, of these, methanol is preferred. However, other inert organic solvents that are capable of 'solubilizing the hydroxylamine reagent also may be used. After completion of the reaction, the solvent is removed as by distillation, the residue dissolved in water and the solution rendered alkaline. The precipitated product that separates is readily recovered by filtration.

The preparation of those compounds represented by structural Formula II, wherein Z is a substituted imino radical (:NOR") and R, R, X and X are as defined, is readily effected by first oxidizing the above ll-hydroxy compound of Step H, wherein R is as defined, following the procedure of Step C hereinabove and then treating the corresponding ll-keto derivative with hydroxylamine reagent as described in Step I. This process may be illus- Stepj/ CHzCHzCHzNHR' wherein R, R, X and X are as previously defined.

The preparation of those compounds of structural Formulae I and II, wherein Z is amino and R', R", X and X are as defined, is accomplished by reducing the corresponding oxime obtained in Step I. The reduction is preferably accomplished using metallic sodium in ethanol, although other conventional reducing agents such as the metal hydrides as well as cataytic hydrogenation may be employed. The desired product may be readily recovered by conventional methods.

The compounds of structural Formula I wherein Z is alkylamino or dialkylamino are readily prepared by alkylating the corresponding amino compound. The alkylation is accomplished in known manner by reductive alkylation employing an appropriate aldehyde or ketone to give the corresponding monoalkylamino derivative. The corresponding dirnethylamino derivative can be prepared employing formaldehyde and formic acid by conventional procedures.

Alternatively, the mono and dialkylamines can be prepared in conventional manner by acylating the primary amine with, for example, acetic anhydride, propionic anhydride r butyric anhydride to form the corresponding amide, and then reducing the latter to the secondary amine using a suitable reducing agent such as lithium aluminum hydride. The dialkylamines can be obtained from monoalkylamines by again acylating and then reducing the secondary amide. The preparation of those compounds of structural Formula I, wherein R and R' are different, can be readily achieved by appropriate selection of the acylating agent, or in the case of the dialkylamines, wherein one of the alkyl radicals is methyl, by subjecting the secondary amine prepared via the acyla'lion and reduction route to reductive alkylation using formaldehyde. The compounds of structural Formula II, wherein Z is alkylamino or dialkylamino, are prepared by treating the ll-keto compound obtained from Step C (wherein R and R" are the same) with a haloformate as described in Step G to form the corresponding ll-keto urethane. The ll-keto urethane is then treated with bydroxylamine or a derivative thereof, as described in Step I, to form the corresponding oxime and the oxime reduced to the corresponding primary amine employing sodium and alcohol or catalytic hydrogenation. The primary amine can then be alkylated using the processes described above and the resulting ll-alkyl or dialkylamino urethane hydrolyzed as described in Step H. This overall process may be represented as follows:

The preparation of those compounds of structural Formula I wherein Z is a substituted sulfonamido radical (NHSO R) and R, R, R, X and X are as defined, is accomplished by treating the corresponding ll-amino derivative with an appropriate sulfonyl halide or sulfonic 12 with respect to the acylation of the ll-hydroxy compounds of structural Formula II, the acylation is carried out employing a salt of the 5,10-epoxy-1l-hydroxyimino- -(3-alkylaminopropyl) derivative.

The compounds of structural Formulas I and II whereanhydride. This process may be illustrated as follows: 5 in Z is the hydrazono radical (=NNH and R, R, X

NH: NHSOzR X X x X (RSO2)20 /R' step I R CH2CHZCH2N\ CHzCHzCHzN RI! RII wherein R, R', R, X and X' are as previously defined and X' are as defined are prepared by reacting the correand Hal represents halogen, preferably chlorine or brosponding ll-keto compound obtained in Step C with hymine. The introduction of the sulfonyl moiety is accomdrazine following the procedure described by D. H. R. plished in conventional manner employing such solvents Barton, R. G. OBrien, and S. Sternhell in J. Chem. Soc., and conditions as are well known in the art. The correp. 470 (1962). sponding sufonylamino derivatives of compounds of struc- The preparation of those compounds of structural Fortural Formula II are readily prepared by dealkylating the mulas I and II wherein Z is CY and an alkyl group re compound obtained from Step I wherein R and R are places hydrogen at the 11 position and R, R", R'", X, X' both lower alkyl and preferably are the same. This process and Y are as defined, is accomplished by acylating the may be illustrated as follows:

NHSOZR NHSOQR wherein R, R, R, X and X are as previously defined.

The preparation of those compounds of structural Formulae I and II, wherein the ll-position contains both a hydroxyl and lower alkyl substituent, wherein R, R", R', X and X are as defined, may be accomplished by treating the corresponding 5-(3-tertiaryaminopropyl)-11- keto compound obtained in Step C with an appropriate Grignard reagent, namely, an alkylmagnesium halide and then hydrolyzing the resulting Grignard adduct following the procedure of Step A. The corresponding secondary aminopropyl derivative of structural Formula II can be prepared by dealkylating the ll-alkyl-ll-hydroxy-5-(3- tertiaryaminopropyl) derivative obtained above following the procedures of Steps G and H or, if desired, the 11- keto-S-(3-alkylaminopropyl) derivative obtained in Step C can be condensed directly with the Grignard reagent and the Grignard adduct hydrolyzed as described above.

The compounds of structural Formula I wherein Z is the radical =NOY and R, R, X, X and Y are as defined are readily prepared by acylating the corresponding 11- hydroxyimino obtained in Step I in the manner described in Step F. The ll-acyloxyimino compounds of structural Formula II are prepared in similar manner from the corresponding ll-hydroxyimino-S-(3-alkylaminopropyl) derivative obtained in Step I except as noted hereinabove corresponding ll-alkyl-ll-hydroxy derivative in the manner described in Step F. However, with respect to the preparation of the ll-alkyl-ll-acyloxy compounds of structural Formula II, the aeylation is carried out in the same manner as previously mentioned for the preparation of the ll-hydroxy and ll-acyloxyimino compounds of structural Formula II, i.e. employing a salt of the 11- alkyl-5,10-epoxy-l l-hydroxy-5-(3-alkylaminopropyl) derivative.

As previously indicated hereinabove, the instant invention includes within its scope the acid addition salts of the compounds represented by structural Formulae I and II, the N-oxides of the compounds represented by structural Formula I, and the acid addition salts of the latter. The acid addition salts are readily prepared by reaction of the free base or N-oxide as the case may be with a suitable acid in known manner. The N-oxides of the compounds represented by structural Formula I are conveniently prepared in conventional manner by treating a compound of structural Formula I, in free base form, with hydrogen peroxide in an inert, organic solvent such as a lower alkanol, preferably methanol.

It will be appreciated by those skilled in the art that the compounds represented by structural Formulae I and II hereinabove, wherein the ll-carbon atom carries two dis- 13 14 similar substituents, exist as geometric isomers. The geofrom magnesium turnings (290 mg., 0.012 g. atom) and metric isomers exist as racemates and resolution into 3-dimethylaminopropyl chloride (1.47 g., 0.012 mole) in enantiomorphs is possible by conventional techniques, 12 ml. of dry tetrahydrofuran following the method of such as fractional crystallization of the salts with optically US. Patent No. 3,046,283. In a nitrogen atmosphere, at active acids. Where Z is hydroxy, the separate geometric solution of cis 30:,125 dihydro2,2-dimethyl-SH-dibenzo isomers can be obtained by starting with the desired iso- [3,4:6,7] cyclohepta[1,2-d] 1,3 dioxol 8 one (1.7 g., mer of the ketone employed in Step A. Such isomers can 0.0061 mole) in 13 ml. of dry tetrahydrofuran is added be obtained utilizing the procedure described in an article dropwise to the stirred solution of the Grignard reagent by G. L. Buchanan et a1., referred to hereinabove. While while cooling in an ice-bath. The dark yellow solution is both isomers possess pharmacological activity, the activallowed to come to room temperature and stirred for 2 ity of one isomer may be substantially greater than the hours. The bulk of the solvent then is distilled at room other. temperature under reduced pressure. The residue is dis- When the ll-position is substituted by an oximino or solved in 25 ml. of benzene, and water, 6 ml., is added hydrazono radical, another type of geometric isomerism dropwise with stirring and cooling. The benzene layer is is possible depending on whether the substituent is syn or 15 decanted from the gelatinous precipitate which then is anti to the oxygen bridge. extracted with three 30 ml. portions of boiling benzene.

It is to be noted that when the carbinols obtained in The combined benzene extracts are washed with water Step A above contain a nuclear substituent, conversion to repeatedly. The benzene is evaporated and the residual the 5,10-epoxy-11-hydroxy derivative (Step B) may give solid crystallized from 95% ethanol. Cis 3a,12B-dihydroeither or both of two compounds depending upon the didimethyl 8 Y P PY Y Y- rection of the ring closure. Thus, when a 6-substituted 8H-dibenzo[3,4:6,7] cyclohepta[1,2-d]-1,3-dioxole is obcarbinol is used, the product may be the 3- and/or 7- tained as white needles, M.P. 181-188 C., in a yield of substituted-5,10-epoxy-1l-hydroxy derivative, and the des- 1.56 g- The P P from another experiignation 3(7) is employed, when a li able, in th folment melts at 189190 C. after recrystallization from lowing examples which describe the preparation of repre- 95% ethanol and from isopropyl alcohol.

sentative compounds encompassed within the scope of the y for 2s 29 3 present invention. N, 3.81. Found: C, 75.12; H, 7.82; N, 4.01.

EXAMPLE 1 Cis 3a,12 3-dihydro-2-phenyl-8H-dibenzo[3,4:6,7]- 30 X MPL 3 cyclohepta[1,2-d]-1,3-dioxol-8-one A solution of cis 10,11-dihydro-10,1l-dihydroxy-SH- dibenzo[a,d]cyclohepten-5-one (2.4 g., 0.01 mole) and ptoluenesulfouic acid monohydrate (25 mg., 0.00013 H1 100 1311- 0f 15 {361116116 is Stirred and heated to By following the procedure of Example 2, but using an {efiuXlflg- The f q 1S dfstllled Slowly and afteT PP equimolecular quantity of cis 3a,12,8-dihydro-2-phenyllrnately 5 ml. of distillate is collected, 5 ml. of freshly disgl-LdibenzMad] 1 2 -1 3 i 1 g one i filled heezalgiehyde 1S adfled to the mlxwre- Stirring and stead of the cis 3a,12B-dihydro-2,2-dirnethyl-8H-dibenzoslow distillation are continued for 1 hour. After the addi- 3 4; 1 2 1 3 1 gthere i b. non of 1 ml. of pyridine, the mixture is evaporated to drymi d i 3 ,12,3-dihydro-8-(3-dimethylaminopro 1) ness under reduced pressure. Crystallization of the solid hydroxy 2 pheny1 8H dibenzo[3,4:6,7]cyc1ohepta[1, resldue f ,absolufe ethanol glvfis the Pwduct, M- 2-d]-1,3-dioxole as a white crystalline solid, MP. 155- 167-175 m a yield (40%) An analytlcal 161 C., in a yield of 71%. Repeated recrystallizations sample melts at 175-1765 C. after repeated recrystalfrom 95% ethanol Give an analytical sample lizations from absolute ethanol. 0

F g g 313 E; C22H16O3= 80-47; H, Analysis.Calcd for C H NO c, 78.04; H, 7.04;

t N, 3.37. Found: c, 78.09; H, 7.21; N, 3.42.

EXAMPLE 2 Cis 31,12 8 dihydro 2,2 dimethyl-8-(3-dimethylaminopropyl) 8 hydfoxy 8H dibenzoBAfiJkyclo Following the procedure of Example 2, the products hepta[lz'd]'l3-dloxole enumerated below are obtained using the ketone of Ex- 3-dimethylaminopropylmagnesium chloride is prepared ample 2 and the Grignard reagent designated below.

Cis 3 05,12/3-dihYd1'0-8- (3-dimethylaminopropyl) -8-hydroxy-2-phenyl-8H-dibenzo[3,41 6,7] cyclohepta[ 1,2-d] 1,3 -dioXole EXAMPLE 4 Grignard reagent Product Mlethylaminopropylmagneslum chloride cis 8-(3-diethylaminopropyl)-3a,12B-dihydro-Z,2-dimethyl-B-hydroxy-8H-dibenzo[3,4:6,7]-

cyclohepta[l,2-d]-1,3-dioxole.

3-(l-pyrrolidyD-propylmagnesium chloride Cis 3a,12 3 dihydro 2,2-dimethy1-8-hydr0xy-8-[3-(l-pyrrolidyl)-propyl]-8H-dibenzo[3,4:-

6,7]cyclohepta[1,2-d]-1,3-dioxole.

3-(l-piperidyl)-propylmagnesium chloride Cis 31x,1ZB-dihydro-Z,2-cimethyl-8-hydroxy-8-[3-(l-piperidyl)-propyl1-8H-dlbenzo[3,4:6,7]-

cyclohepta[1,2-d]-1,3-dioxole.

3-(l-ethylt-piperazinyD-propylmagnesium chloride Cis 3a,12B-dihydro-2,2-dimethyl-8-[3-(1ethy1-4-piperazinyl)-propyl]-8-hydroxy-8H-dibenzo-[3,4:6,7]cyclohepta[1,2-d]-1,3-dioxole.

3-(4-morpholinyD-propylmagnesium chloride Cis 3a,12fl-dihydro-2,2-dimethyl-8-hydroxy-8-[3-(4-morpholiuyl)-propyl]-8H-dibenzo[3,4:-

6,7]cyclohepta[1,2-d]-1,3-dioxo1e.

3-(N-ethyl-N-methylamino)propylmagnesium chloride Cis 3a,12fi-dihydro-2,2-dlmethyl-8-[3-(N-ethyl-N-methylamino)-pr0pyl]-8hydroxy-8H- 1 EXAMPLE 5 Following the procedure of Example 2, the products enumerated below are obtained using the Grignard reagent of Example 2 and the ketone designated below Ketone Product Cis SaJQB-dihydro-2,2-dimethyl-fimethylsulfonyl-BH-dibenzo[3,416,7]cyclohepta[1,2-d]-1,3-dioxol-8-one.

Cis 3a,126-dihydro-8-(3-dimethylaminopropy1)-8-l1ydroxy-8H-dibenzo[3,4; 6,7]cyclohepta[1,2-d]-1,3-dioxole.

Cis 3a ,12 'i-dihydro-8 (3-dirnethylaminopropyl)-8-hydroxy-2-methyl- SH-dibenzoBA 6,7]cyclohepta[1,2-d]-1,3-dioxole.

Cis 3a,125-dihydr0-8-(3-dimethylaminopropyl)-2-ethyl-8-hydroxy-2- methyl-8H-dibenzo-[3,4: 6,7]cyclol1epta[1,2-d]-1,3-dioxole.

Cis 6-chl0ro-3a,12fl-dihydro-2,2-dimethyl-8-(ii-dimethylaminopropyl) 8-hydroxy-8H-dibenzo[3,4: 6,7]cyclohepta[1,2-d]-1,3-dioxole.

EXAMPLE 6 Cis 10,11-dihydro-5-(3-dimethylaminopropyl)-5,10- epoxy-l 1-hydroxy-5 H-dibenzo [a,d] cycloheptene A solution of cis 3oz,l2,8 dihydro-2,2-dimethyl-8-(3- dimethylaminopropyl) 8-hydroxy-8H-dibenzo[3,416,71- cyclohepta[1,2-d]-1,3-dioxole (2.95 g., 0.008 mole) and p-toluenesulfonic acid monohydrate (3.0 g., 0.0158 mole) in 300 ml. of absolute methanol is heated to refluxing for 4 hours. The solution is neutralized with 16 ml. of 1 M potassium hydroxide in methanol and then the solvent is distilled under reduced pressure. The residue is partitioned between benzene and water and the aqueous layer re-extracted twice with benzene. The combined benzene extracts are washed with water, dried by filtration through paper, and then evaporated to dryness under reduced pressure. Crystallization of the residual solid from 60% ethanol gives the product, M.P. 145- 152 C., in a yield of 1.9 g. (81%). An analytical sample melts at 151153 C. after repeated crystallizations from cyclohexane.

Analysis.Calcd for C H NO C, 77.64; H, 7.49; N, 4.53. Found: C, 77.67; H, 7.70; N, 4.52.

EXAMPLE 7 Cis 10,1l-dihydro-S-(3-dimethylaminopropyl)-5,10- epoxy-1l-hydroxy-SH-dibenzo[a,d]cycloheptene A solution of cis 3a,12fi-dihydro-8-(3-dimethylaminopropyl) 8 hydroxy 2 phenyl 8H-dibenzo-[3,4:6,7] cyclohepta[1,2-d]-1,3-dioxole (415 mg, 0.001 mole) and p-toluenesulfonic acid monohydrate (380 mg, 0.002 mole) in ml. of absolute methanol is heated to refluxing for 8 hours. The cooled solution is made basic with 5 ml. of 1 M potassium hydroxide in methanol and the solvent is distilled under reduced pressure. The residue is partitioned between benzene and water and after re-extraction of the aqueous phase with benzene, the combined benzene extracts are washed with water and dried by filtration through anhydrous sodium sulfate. Evaporation of the benzene under reduced pressure leaves an oily residue which solidifies upon trituration with ether, yielding 200 mg. (65% M.P. 137144 C. A purified sample is identical in melting point (149l52 C.), mixture melting point and infrared spectrum to cis 10,11-dihydro-5- (3 dimethylaminopropyl) 5,10-epoxy-1l-hydroxy-SH- dibenzo[a,d]cycloheptene, prepared as in Example 6.

EXAMPLE 8 Employing the procedure of Example 6, the products enumerated below are obtained using the products enucis 10,11-dihydro-5,10-epoxy-11-hydroxy-5-[3-(1- pyrrolidyl) -propyl] -5H-dibenzo [a,d] cycloheptene cis 10,11-dihydro-5,10-epoxy-11-hydroxy-5-[3-(1- piperidyl) -propyl -5H-dibenzo [a,d] cycloheptene cis 10,11-dihydro-5,10-epoxy-5-[3-(1-ethyl'4-piperazinyl)- propyl] -1 1-hydroxy-5H-dibenzo[a,d] cycloheptene cis 10,11-dihydro-5,10-epoxy-11-hydroxy-5-[3-(4- morpholinyl) -propyl] -5H-dibenzo [a,d] cycloheptene cis 10,11 dihydro 5,10 epoxy 5 [3 (N ethyl N methylarnino) propyl] 11 hydroxy 5H dibenzo [a,d] cycloheptene cis 10,11 dihydro 5 (3 dimethylaminopropyl) 5,10- epoxy 11 hydroxy 3(7) methylsulfonyl 5H dibenzo [a,d] cycloheptene cis 3(7) ch-loro 10,11 dihydro 5 (3 dimethylaminopropyl) 5,10 epoxy 11 hydroxy 5H dibenzo [a,d] cycloheptene cis 10,1l-dihydro-S-(3-dimethylaminopropyl)-3 (7)- dimethyl-sulfamoyl-S,10-epoxy-1 1-hydroxy-5H- dibenzo [a,d] cycloheptene EXAMPLE 9 Trans 311,128 dihydro-2,2-dimethyl-8-(3-dimethylaminopy )-8-hydrox 8H dibenzo[3,4:6,7]cyclohepta [1,2-d]-1,3-dioxole 3-dimethylaminopropylmagnesium chloride is prepared from magnesium turnings (4.05 g., 0.166 g. atom) and 3-dimethylaminopropyl chloride (20.2 g., 0.166 mole) in 150 ml. of dry tetrahydrofuran, following the method of US. Patent No. 3,046,283. In a nitrogen atmosphere, a solution of trans 3a,12,8-dihydr0-2,2-dimethyl-8H-dibenzo [3,4:6,7]cyclohepta[l,2-d] 1,3 dioxol-S-one (23.2 g., 0.083 mole) in ml. of dry tetrahydrofuran is added dropwise to the stirred solution of the Grignard reagent while cooling in an ice-bath. The mixture is allowed to come to room temperature and stirred for 2 hours. The bulk of the solvent then is distilled below 50 C., under reduced pressure. The residue is dissolved in ml. of benzene, and water, 20 ml., is added dropwise with stirring and cooling. The benzene layer is decanted from the gelatinous precipitate which then is extracted with four 100 ml. portions of boiling benzene. The combined benzene extracts are washed with Water and extracted with three 100 ml. portions of 0.5 M citric acid. The acid extract is made basic with sodium hydroxide and the oily base that separates is extracted into benzene. After Washing the combined extracts with water and drying over anhydrous sodium sulfate, the benzene is evaporated and the product obtained as a viscous yellow oil in a yield of 29.5 g. (96%).

The base may be converted to the hydrogen oxalate from a mixture of benzene and cyclohexane affords the salt by treating an ethereal solution with a solution of white crystalline product, M.P. 156160 C., in a yield oxalic acid (10% excess) in isopropyl alcohol. The trans of 18 g. (73%). The pure product melts at 157158 C. 3u,12,6-dihydro 2,2 dimethyl 8 (3-dimethylaminoafter recrystallization from benzene and sublimation at propyl) 8 hydroxy 8H dibenzo [3,4:6,7]cyclo- 140 C. and 0.01 mm. hepta[1,2-d]-1,3-dioxole hydrogen oxalate is obtained as 5 y f C H NO C, 77.64; H, 7.49; a white crystalline solid, M.P. 169172 C., dec. Repeated Found: 77.73;

recrystallizations from mixtures of isopropyl alcohol and absolute ether give the product, M.P. 171173 C., dec. EXAMPLE 13 Analysis calcd for C23H29NO3C2H2O4; C, 6552; Employing the procedure of Example 12, the products H, 6 33 Found; C, 53 H, 7 10 enumerated below are obtained using the products enumerated in Examples 10 and 11 in place of the dioxole EXAMPLE 10 used in Example 12.

Following the procedure of Example 9, the products trans 5-(3-diethylaminopropyl)-10,11-dihydro-5,10- enumerated below are obtained using the ketone of Ex- 15 epoxy-1 1-hydroxy-5H-dibenzo1[a,d]cycloheptene ample 9 and the Grignard reagent designated below. cycloheptene Grignard reagent Product 3-diethylaruinopropylmagnesium chloride Trans 8-(3-di t Y amin0-pr0pyl)-3a,128-dihydro-2,2-dimethyl-8-hydroxy-8Hdibenzo- [3,4: 6,7]cyclo-hepta[1,2-d]-1,&dioxole.

3-(l-pyrrolidyl)-propy1magnesium chloride Tr n 3a,12B-dihydr0-2,2-dimethyl-8-hydroxy-8-[3-(1- yrrolid 1- r0 I-SH-dibenzm [3,426,7]cyclo-hepta[1,2-d]-1,3-dioxole. p y) p py] 3-(ii eridyD-propylmagnesium chloride Tran 3:! 12/ -dihydr0-2,2-dimethyl-S-hydroxy-S[3-(1- i eridyl)-pr0 l-SH-dibenzo- [3,4:6,7lcycl0-hepta[1,2-d]-1,8-di0x0le. p p py] 3-(i-ethyl-qt-piperazinyD-propylmagnesium chloride Trans 3rx,l2fl-dihydro-2,2-dimethyl-8-[3-(1-ethyl-4- i erazinyl ro l-S-h drox -8 dibenzo-[3,4:6,7]cyclohepta{1,2-d]-1,3-dioxo1e. p p p Dy] y y 3-(4-morpholinyD-propyl magnesium chloride Tr n 3a,12B-dihydr0-2,2-dimethyl-8-hydroxy-8-[3-(4-morpholiny1)-propyl]-8H-dibenzo- 3-(N-ethyl-N-methylamino)-propylmagnesium chloride Trans3a,126-dihydro-2,2-dimethyl-8-[3-(N-ethy1-N-meth lamino r0 l-8-h drox 8H-dibenzo[3,4:6,7]cycloheptaI1,2-d]-1,3-dioxo1e. y p Dy] y y EXAMPLE 11 trans 10,11-dihydro-5,10-epoxy-11-hydroxy-5-[3-( l-pyr- Following the procedure of Example 9, the products rolidyl)'PrOPYl]'5H'dibenZ[a:d]cycloheptene enumerated below are obtained using the Grignard rey -i p y- Y yagent of Example 9 and the ketone designated below. (l-piperidyl)-propyl]-5H-dibenzo[a,d]cycloheptene Ketone Product Trans 3a,12B-dihydro-8H-dibenzo[3,4:6,7]cyclohepta-[1,2-d]-1,3-dioxol-8-one Trans 3a,12B-dihydro-8-(3-dimethylarninopropyl)-8-hydrox H.

Trans 3a,12 341ihydro-2-methy1-8H-dibenzo[3,4:6,71-cyclohepta[1,2-d]-1,3-dioxo1- Trans3a,126-(1ihydro-8-(3-dimethylaminopropyD-S-hydroxy-Z- sona. methyl-8H-dibenzo[3,4:6,7]cyclohepta-[1,2-d]-1,3-dioxole.

Trans 2-benzyl-3a,12B-dihydro-8H-dibenzo[3,4z6,7]cyclohepta[1,2-d]-1,3-dioxol-8- Trans 2-benzyl-3a,12fl-dihydro-8-(3dimethyl-aminopropyl)-8-hyone. droxy-8H-dibenzo[3,4z6,7]cyclohepta[1,2-d]-l,3-dioxole.

Trans 3a,12B-dihydro-Z-ethyl-2-methy1-8H-dibenzo[3,4:6,7]cyclohepta[1,2-d]-1,3- Trans 3a,125-dihydro-8-(S-dimethylaminopropyl)-2-ethy1-8-hydroxydioxol-B-one. 2-methyl-8H-dibenzo-[3,4: 6,7]cyclohepta[1,2-d]-1,3-dioxole.

Trans 3a,12fi-dihydro-2,Q-dimethyl-EvmethylsuHony1-8H-dibenzo[3,4:6,7]cyclo- Trans3a,12fl-dihydro-2,2-dimethyl-8(3-dimethyl-aminopropyD-8- hepta[1,2-d]-1,3-dioxo1-8-one. lydrolxy-fi-methylsulfonyl-SH-dibenzo-[3,4:6,7]cyclohepta[1,2-d]-l,3-

Trans 6-ch1or0-3a,12B-dihydro-2,2 dimethyl-8H-dibenzo-[3,4:6,7lcyclohepta[l,2- Trans 6-ehloro-3a,125-dihydro-2,2-dirnethyi-S-(3-dimethylaminoprod]-1,3-dioxo1-8-one. py1)-8-hydr0xy-8H-dibenzo-[3,4:6,7]cyclohepta-[1,2-d]-1,3-dioxole.

Trans 3a,12B-dihydro-2,2-dimethyl-6-d1methyl-su1famoyl-S-H-dibenzo-{3,4: 6,71- Trans 3a,12fl-dihydr0-2,2-dimethy1-8-(3-dimethyl-am1nopropy1)-6-dicyelohepta[1,2-d]-1,3-diox01-8one. ingiiihiyi-slulfamoyl-8-hydroxy-8H-dibenzo[3,4: 6,7]cyclo-hepta[1,2-d]- EXAMPLE 12 trans 10,11-dihydro-5,10-epoxy-5-[3-(1-ethyl-4-piper- Trans 10,11-dihydro-5-(3 dimethylaminopropyl) 5,10- azmyn'propyn'l1'hydrOXy'5H'd1benZo[ad] epoxsf 11 hydroxy 5H when. [and] cych.)heptene trans 10,11-dihydro-5,10-epoxy-11-hydroxy-5-[3-(4- A solution of trans 3a,12,8-d1hydro-2,.2-d1methyl-8-(3- morpholinyl) pr0py1] 5H dibenZo[ad] dlmethylaminopropyl)-8-hydroxy-8H d1benzo[3,4:6,7]- trans 1O 11 dihydro 5 y cyclohepta[1,2-d]-1,3-d1oxole (29.4 g., 0.08 mole) and methlaminoy r0 drox p-toluenesulfonic acid monohydrate (30.5 g., 0.16 mole) 5 db d t y y in 2.3 l. of absolute methanol is heated to refluxing for 4 l kyc 0 6p 3 hours. The cooled solution is neutralized with 150 ml. trans 101l'dlhydro's'(3'dlmethylammopmpyl) of 1 M potassium hydroxide in methanol and the solvent 51'O"?PXy'1l'hydroxy'3(7)'methylsulfonyl' then is distilled under reduced pressure. The residue is sfl'dlbenzo[ardlcycloheptene partitioned between benzene and 5% aqueous sodium 70 trans l hydroxide and water and the aqueous layer is re-extracted p py P y- Y Y- with three portions of benzene. The combined benzene dibellzohdlcycloheptelle extracts are washed with water, dried by filtration through trans 10,1l-dihydro-5-(3-dirnethylaminopropyl)- anhydrous sodium sulfate, and evaporated to dryness un- 3(7)-dimcthylsulfam0yl-5,10-epoxy-l l-hyder reduced pressure. Crystallization of the residual solid 7 droxy-SH-dibenzo[a,d]-cycloheptene 3,494,935 19 20 EXAMPLE 14 cycloheptene (600 mg., 0.00172 mole) in 3 ml. of dry Cis 1LacetoxYdOl1 dihydro 5 (3 dimethy1amino benzene is added dropwise to a stirred solution of 0.7 ml.

pro py1) 5,10 epOxy 5H dibenzo[a,d] cycloheptene of ethyl chloroformate in 2 ml. of dry benzene. A yellow gum separates, but dissolves upon warming the mixture.

A Solution of Cis y 4 l After stirring for 1 hour at reflux, the mixture is cooled, p py P Y 11 Y Y 5H l fi l 5 diluted with benzene, and washed with 2 N hydrochloric y p f (100294 mole) in 12 of acetic acid, then with water. Evaporation of the benzene under anhydnde 1S heated to YefiuXlng for 41/2 hours The dark reduced pressure leaves the product as an oily residue yellow solution is evaporated to dryness under reduced weighing ty i lly, 650 mg. (92.5%). pressure and the oily residue dissolved in 20 ml. of water containing 1 ml. of 6 N hydrochloric acid. After one 10 EXAMPLE 18 extraction with benzene, the aqueous solution is rendered Following th ro edure of Example 17, the products alkaline With Sodium hydfoXide a y base enumerated below are obtained using the products enutracted into benzene. The washed benzene extract is merated in Examples 1'5 and 16 in place of th dib cycloheptene compound used in Example 17.

cis 5-[3 (N carbethoxy N methylamino)-propyl]- 10,11 dihydro 5,10 epoxy 11 propionyloxy-SH- dibenzo[a,d] -cycloheptene cis 11 butyryloxy 5 [3 (N-carbethoxy-N-rnethyl- 20 amino)-propyl]-l0,11 dihydro 5,10-epoxy 5H- ,dibenzo [a,d] -cyclheptene cis l1 benzoyloxy [3 (N-carbethoxy N methylamino)-propyl] 10,11 dihydro 5,10 epoxy-5H- dibenzo[a,d]-cycloheptene cis 11 acetoxy 5 [3 (N-carbethoxy N ethyl- Analysis.Calcd for C22H25NO3-C2H2O4: c, 65.29; amino) propyl] 10,11 dihydro P dibenzo a,d] cycloheptene H, 6.16; N, 3.17. Found: C, 65.27; H, 6.40; N, 3.06.

C18 11 acetoxy 5 [3 (N carbethoxy N methyl- EXAMPLE amino) propyl]-10,l1 dihydro 5,10 epoxy-3(7)- Following the procedure of Example 14, the products methylsulfonyl- H- y p enumerated below are obtained employing the acylating C s 11 ace xy 3(7) C O 5 [3 (N-carbethoxy agents designated below in place of acetic anhydride used N-rnethylamino) propyl] 10,11 dihydro-5,10- in Example 14. epoxy-SH-dibenzo[a,d]cycloheptene evaporated under reduced pressure, leaving the product as an oily residu weighing, typically, 600 mg. (84%).

The base may be converted to the hydrogen oxalate salt by treating a solution in isopropyl alcohol with a solution of oxalic acid 10% excess) in isopropyl alcohol. Cis 11 acetoxy 10,11 dihydro 5 (3-dimethylaminopropyl)-5,l0-epoxy-5H-dibenzo[a,d]-cycloheptene hydrogen oxalate is obtained as a white crystalline solid, M.P. l7l173 C., dec. Repeated recrystallizations from isopropyl alcohol and from mixtures of absolute ethanol and absolute ether give the product, M.P. 173-175 C., dec.

Acylating agent Product Propionic anhydride cis 10,11-dihydro-5-(3-din1ethylaminopropyD-5,10-epoxy-1L proplonyloxy-5H-dibenzo[a,d]cycloheptene.

Butyryl chloride/pyridine. Cis 11-butyry1oxy-10,11-dlhydro-5-(3-dlmethylaminopropyl)-5,10-epoxy-5H-dibenzo[a,d]cyel0heptene.

Benzoyl chIorlde/pyridine. Cis 1l-benzoyloxy-w,11-dlhydro-5-(3dtmethy1am1nopropyl)-5,10-epoxy-5H-dibenzo[a,d]cyclohepteue.

Caproyl chlorldelpyrldinm Cis 1l-caproyloxy-IO,1l-dihydro-5-(8-dimethylamlnopropyl)-5,IO-epoxy-5H-dibenzo[a,d]cycloheptcue.

cis 11 acetoxy 5 [3 (N-carbethoxy N methyl- EXAMPLE 16 amino) propyl]-l0,l1 dihydro 3(7) dimethyl- Following the procedure of Example 14, the products sulfamoyl 5,10 epoxy 5H d1benzo[a,d]cycloenumerated below are obtained employing, in place of cis heptene 10,11 dihydro 5 (3 dimethylaminopropyl) 5,10- (215 11 caproyloxy '5 [3 (N carbethoxy-N-methylepoxy-1l-hydroxy-SH-dibenzo[a,d]cycloheptene, the reamino) propyl]-10,l1 dihydro 5,10 epoxy 5H- actants designated below. dibenzo[a,d]cycloheptene Reactant Product Cis 5-(3.diethy1amihopropyl)40,11-dihydro-5,10-epoxy-1l-hydroxy- Cis 11-acetoxy-5-(3-diethylaminopropyl)-10,11-dihydro- 5H-dibenzo[a,d]-oycloheptene. 5,10epoxy-5H-dibenz0[a,d]eycloheptene. Cis 10,11-dihydro-5-(3dimethylaminopropyl)-5,1(%epoxy-11-hydroxy- Cis 11-acetoxy-10,11-dihydro-5-(dimethylaminopropyD- 3(7)-methylsultonyl-SH-dibenzo[a,d]cycloheptene. g,10ep0xy-3(7)-methylsulfony1-5H-dibenzo[a,d]cyclo- ED ene.

Cis 8(7) -ch1oro-10,11-dihydro-5-(3-dimethylaminopropyl) -5,10-epoxy- Cis 11-acetoxy-3(7)-chloro-10,11-dihydro-5-(3-dimethy1- ll-hydroxy-fiH-dibenz0[a,d]cyc1oheptene. amino'propyl)-5,10-epoxy-5H-dibenzo[a,d]cycloheptene.

Cls 10,1l-dihydro-5-(3-dimethylamlnopropyl)-3(7)-dlrnethylsulfamoyl- Cis 11-acetoxy-10,11-dihydro-5-(3-dimethylaminopro y1)- 5,10-epoxy-11-hydroxy-5H-dibenzo[a,dleyeloheptene. 3(7)-dimetl1y1sultamoy1-5,10epoxy'5H-dibenz0[a,d

cycloheptene.

EXAMPLE 17 Cis ll acetoxy 5 [3 (N carbethoxy N methyl- EXAMPLE 19 amino) propyl] 10,11 dihydro 5,10 epoxy 5H- dibenzo[a,d]cycloheptene Following the procedure of Example 17, the products A solution of cis 11-acetoxy-10,11-dihydro-5-(3-dienumerated below are Obtained employing the halo methylaminopropyl) 5,10 epoxy SH dibenzo[a,d] 7 formate designated below.

Haloformate Product Benzyl chloroformate Cis 11-acetoxy-5-[3-(N-carbobenzoxy-N-methylamino)- propyl]-10,11-dihydro-5,10-epoxy-5H-dibenzo[a,d]eyeloheptene.

Propyl chlorf0rmate Cis 1l-aeetoxy-5-[3-(N-earbopropoxy-N-methylamino) -propyl]- 10,11-d1hydro-5,10-epoxy-5H-dibenzo[a,dlcycloheptene.

EXAMPLE 20 Cis 10,11 dihydro 5,10-epoxy-1l-hydroxy-5-(3- methyl-aminopropyl) -5H-dib enzo [a,d] cycloheptene A solution of the crude urethane obtained in Example 17 (650 mg., 0.00159 mole) and potassium hydroxide (500 mg., 0.0089 mole) in ml. of n-butyl alcohol is stirred and heated to refluxing in a nitrogen atmosphere for 7 hours. The solvent is evaporated under reduced pressure and the residue partitioned between benzene and water. After two re-extractions of the aqueous phase, the combined benzene extracts are washed with water and then extracted with ml. and 10 ml. portions of 0.5 M citric acid. The benzene layer then is washed with Water. Evaporation of the solvent under reduced pressure leaves the neutral materials, cis 5-[3-(N carbethoxy-N-methylamino)-propyl]-l0,1l dihydro 5,10 epoxy ll-hydroxy 5H dibenzo-[a,d]cycloheptene, as an oily residue weighing, typically 300 mg. The citric acid extract is rendered alkaline with sodium hydroxide and the oily base extracted into benzene. The washed benzene extract is evaporated to dryness under reduced pressure. Crystallization of the residue from absolute ether gives the product as a white crystalline solid, M.P. 128130 C., in a yield of 110 mg.

A solution of the neutral material and potassium hydroxide (250 mg., 0.0045 mole) in 4 ml. of n-butyl alcohol is stirred and heated to refluxing in a nitrogen atmosphere for 10 hours. The reaction mixture is worked up as described above and the basic material crystallized from absolute ether to obtain additional product, M.P. 126-128 C., in a yield of 70 mg. The combined products (180 mg., are purified by recrystallization from absolute ether and sublimation at reduced pressure gives an analytical sample which melts at 138-139 C.

Analysis.Calcd for C H NO C, 77.25; H, 7.17; N, 4.74. Found: C, 77.07; H, 6.95; N, 4.91.

Reaetant Trans 5-(8-diethylaminopropyl)-10,11dihydro-5,10epoxy-11-hydroxy-5H- dibenzo[a,d]cycloheptene.

Trans 10,lldihydro-S-(3-dimethylaminopropyl)-5,10-epoxy-11-hydroxy-3(7)- methylsulionyl-SH-dibenzo[a,d]cycloheptene.

Trans 10,11-dihydro 5 (3-dimethylaminopropyl)-3 (7)-dlmethylsulfamoyl-5,10

epoxy11hydroxy-5H-dibenzo[a,d]cyeloheptene.

EXAMPLE 21 Following the procedure of Example 20, the products enumerated below are obtained employing the products enumerated in Examples 18 and 19 in place of the urethane used in Example 20.

EXAMPLE 22 Trans 11-acetoxy-10,11-dihydro-5-(3-dimethylaminopropyl )-5-10-exopy-5H-dibenzo a,d] cycloheptene By replacing the cis 10,11-dihydro-5-(3-dimethylaminopropyl)-5,10- epoxy 11 hydroxy-SH-dibenzo[a,d]cyclo heptene used in Example 14 with an equimolecular amount of the trans isomer and following substantially the same procedure described in Example 14, there is obtained trans 11-acetoxy-10,1 l-dihydro-S (3-dimethylaminopropyl)-5 ,10 epoxy 5H dibenzo [a,d] cycloheptene. The yield of white crystalline base, M.P. 116.5-" C., is 79%. An analytical sample melts at 126 C. after recrystallization from petroleum ether.

Analysis.Calcd for C H NO C, 75.18; H, 7.17; N. 3.99. Found: C, 74.93; H, 7.04; N, 3.94.

EXAMPLE 23 Following the procedure of Example 22, the products enumerated below are obtained employing the acylating agents enumerated in Example 15.

trans 10,11-dihydro-5-(3 -dimethylaminopropyl) -5,10-

epoxy- 1 1-propionyloxy-5-H-dibenzo [a,d] cycloheptene trans 11-butyryloxy-10,1 l-dihydro-S- 3-dimethylaminopropyl) -5,10-epoxy-5H-dibenzzo [a,d] cycloheptene trans l 1-benz0yloxy-10,1 1-dihydro-5- 3-dimethylaminopropyl-5,10-epoxy-5H-dibenzo[a,d]cycloheptene trans 11-caproyloxy-10,1l-dihydro-S-(3-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo [a,d] cycloheptene EXAMPLE 24 Following the procedure of Example 22, the products enumerated below are obtained employing in place of trans 10,11 dihydro 5 (3 dimethylaminopropyl)-5,l0- epoxy-1 l-hydroxy-SH-dibenzo [a,d] cycloheptene, the reactants designated below.

Product Trans 11-acetoxy-5-(B-dlethylaminopropyl)-10,11-dihydro-5,10-

epoxy-5Hdibenzo[a,d]cycloheptene.

Trans 11-acetoxy-10,1l-dihydro-5(El-dimethylamlnopropyl)5,10- epoxy-3(7)-methy1sulfonyl-5H-dibenzoIa,d]cyeloheptene.

Trans 11-acetoxy-3(7) chloro-10,11-dihydro-M3-dimethylarninopropyl) -5,10-ep0xy-5H-dibenzo[a,d]cye1oheptene.

Trans 11-acetoxy-10,11-dihydro-5-(3-dimethylamlnopropyl)-3(7)- dimethylsulfamoyl-S,10'epoxy-5H-dibenzo[a,d]eyeloheptene.

EXAMPLE 25 Trans 11-acetoxy-5-[3-( N carbethoxy-N methylamino)- propyl]-10,11 dihydro-5,10-epoxy 5H-dibenzo[a,d]- cycloheptene Trans 11 acetoxy 10,1l-dihydro-S-(S-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo[a,d]cycloheptene, 5.5 g. (0.0157 mole), is added in small portions with stirring to ml. of ethyl chloroformate cooled in an ice-bath. The mixture is stirred in the cold for 1% hours, then heated to refluxing for 16 hours. Excess ethyl chloroformate is distilled under reduced pressure and the oily residue treated with benzene and the mixture evaporated to dryness under reduced pressure. This treatment is repeated and the residue finally is partitioned between benzene and water. The benzene layer is washed with water, 0.5 M citric acid, and water, dried by filtration through anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Crystallization of the oily residue from ether-petroleum ether gives the product, M.P. 75- 76 C., a yield of 2.4 g. A second crop of 2.0 g., M.P. 72-73" C., is obtained from the mother liquor. A purified sample melts at 7778 C. after recrystallization from a mixture of absolute ether and petroleum ether.

Analysis.-Calcd for C H NO C, 70.40; H, 6.65. Found: C, 69.78; H, 6.80.

EXAMPLE 26 Following the procedure of Example 25, the products enumerated below are obtained employing the products enumerated in Examples 23 and 24 in place of the dibenzocycloheptane compound used in Example 25.

trans 5 -[3-( N-carbethoxy-N-methylamino -propyl] -10,1 1- dihydro-5,l-epoxy-1 l-propionyloxy-H-dibenzo[a,d] cycloheptene trans 1 1-butyryloxy-5- 3- N-carbethoxy-N-methylamino propyl]-10,11-dihydro-5,10-epoxy-5H-dibenzo[a,d]- cycloheptene trans 1l benzoyloxy-5-[3-(N-carbethoxy-N-methylamino)-propyl]-10,1l-dihydro-S,10-epoxy-5H-dibenzo- [a,d] cycloheptene trans 1 1-acetoxy-5-[3-(N-carbethoxy-N-ethylamino)- propyl] -10,1 1-dihydro-5 ,10-epoxy-5H-dibenzo[a,d]- cycloheptene trans 1 1-acetoxy-5-[3- (N-carbethoxy-N-methylamino propyl]-10,1 1-dihydro-5,10-epoxy-3 (7) -methylsulfonyl-SH-dibenzo [a,d] cycloheptene trans 11-acetoxy-3 (7 -chloro-5- 3-(N-carbethoxy-N- methylamino)-propyl]-10,11-dihydro-5,10-epoxy- SH-dibenzo [a,d] cycloheptene trans 1 l-acetoxy-S- 3- N-carbethoxy-N-methylamino propyl]-10,1'1-dihydro-3 (7)-dimethylsulfamoyl- 5,10-epoxy-5H-dibenzo[a,d]cycloheptene trans 1 1-caproyloxy-5-[3-(N-carbethoxy-N-rnethylamino) -propyl] -l0,l l-dihydro-5-10-epoxy-5H- dibenzo [a,d] cycloheptene EXAMPLE 27 Following the procedure of Example 25, the products enumerated below are obtained employing the haloformate enumerated in Example 19.

24 crystalline solid, M.P. l28129 C., in a yield of 1.5 g. (51% An analytical sample melts at 129-130 C. after sublimation at 115 C. and 0.1 mm.

Analysis.Calcd for C H NO C, 77.25; H, 7.17; N, 4.74. Found: C, 77.33; H, 7.20; N, 4.94.

EXAMPLE 29 Following the procedure of Example 28, the products enumerated below are obtained employing the products enumerated in Examples 26 and 27 in place of the urethane used in Example 28.

trans 10,11-dihydro-5,10-epoxy-l l-hydroxy-S- 3 -methylaminopropyD-SH-dibenzo a,d]cycloheptene trans 10,1l-dihydro-S,10-epoxy-5-(3-ethylaminopropyl)- l l-hydroxy-5H-dibenzo[a,d]cycloheptene trans 10,11-dihydro-5,10-epoxy-11-hydroxy-5(3-methylaminopropyl) -3 (7 -methylsulfonyl-SH-dibenzo- [a,d] cycloheptene trans 3 (7 -chloro-1 0, l l -dihydro-5,1 O-epoxy-l l-hydroxy- 5- (3 -methylaminopropyl) -5H-dibenzo [a,d cycloheptene trans 10,1l-dihydro-3 (7)-dimethylsulfamoyl-5,l0-epoxy- 1 l-hydroxy-S- (3-methylaminopropyl -5H-dibenzo[a,d] cycloheptene EXAMPLE 30 10,11-dihydro-5-(3-dimethylaminopropyl)-5,10-epoxy- 11-keto-5H-dibenzo[a,d]cycloheptene A solution of trans 10,1l-dihydro-S-(3-dimethylaminopropyl) 5,10-epoxy ll-hydroxy 5H-dibenzo-[a,d] cycloheptene (6.18 g., 0.02 mole) and 60 ml. of freshly distilled cyclohexanone in 600 ml. of dry toluene is heated to boiling and 250 ml. of toluene is distilled. Slow distillation is continued while a solution of aluminum isopropoxide (8.0 g., 0.039 mole) in 400 ml. of dry toluene is added dropwise over a 1 hour period and for an additional 30 minutes. The mixture is cooled in ice and hydrolyzed by the addition of 100 ml. of a saturated aqueous solution of Rochelle salt. The aqueous layer is separated and re-extracted twlce w1th benzene. After washing with water, the combined organic layers are extracted with 200 ml. of 0.5 M citric acid. The citric acid Halotormate Product B enzyl chI0roIormate Trans 11acetoxy5-[3-(N-carbobenzoxy-N-methylamlno) propyl]-10,1l-dihydro'fi,10-epoxy-5H-dibenzo[a,d]cycloheptene.

Phenyl ch10rof0rmate Trans 1l-acetoxy-5-[3-(N-carbophenoxy-N-methylamino)- propyl]-10,11-dihydro-5,10-epoxy-5H-dibenzo[a,d]cyc1oheptene.

Propyl chloroforniate- Trans 1l-acet0x31'5-[3-(N-carbopropoxy-N-methylamino)- propyl]-10,11-dihydro-5,IO-epoxy-SH-dibenzola,d]cycloheptene.

EXAMPLE 28 A solution of trans 1l-acetoxy-S-[3-(N-carbethoxy-N- methylamino)-propyl]-10,1l-dihydro 5,10-epoxy 5H- dibenzo[a,d]cyc1oheptene (4.1 g., 0.01 mole) and potassium hydroxide (20 g., 0.358 mole) in 100 ml. of nbutyl alcohol is stirred and heated to refluxing in a nitrogen atmosphere for 11 hours. The solvent is evap orated under reduced pressure and the residue partitioned between benzene and water. After two re-extractions of the aqueous phase, the combined benzene extracts are washed with water and then extracted with three 100 ml. portions of 0.5 M citric acid. The citric acid extract is rendered alkaline with sodium hydroxide and the oily base extracted into benzene. The washed benzene extract is dried by filtration through anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the oily residue from a mixture of absolute ether and petroleum ether gives the product as a White extract is cooled in an ice-bath, rendered alkaline with sodium hydroxide and the oily base extracted into benzene. The washed and dried benzene extract is evaporated under reduced pressure to give the product as a crystalline residue, M.P. 67-69 C., in a yield of 6.05 g. (98.5%).- An analytical sample melts at 7678 C. after repeated recrystallizations from hexane.

AnaIysis.Calcd for C H NO C, 78.14; H, 6.89; N, 4.56. Found: C, 78.22; H, 6.99; N, 4.49.

EXAMPLE 3 1 Following the procedure of Example 30, the products enumerated below are obtained employing the products enumerated in Example 13 in place of the dibenzocycloheptene used in Example 30.

10,1 l-dihydro-S-(3-diethylaminopropyl)-5, 10-epoxy-1 lketo-SH-dibenzo [a,d] cycloheptene 10,11-dihydro-5,IO-epoxy-l l-keto-5-[3-( 1-pyrrolidyl)- propyl] -5H-dibenzo [a,d] cycloheptene 10,1l-dihydro-5,10-epoxy-11-keto=5-[3-(1-piperidyl)- propyl]-SH-dibenzo [a,d] cycloheptene 2 10,1 1-dihydro-5,10-epoxy-5-[3-(1-ethy1-4-piperazinyl)- propyl]-11-keto-5H-dibenzo[a,d]cycloheptene- 10,11dihydro-5,10-epoxy-11-keto-5-[3-(4-morpholinyl)- propyl] -5H-dibenzo [a,d] cycloheptene l0,11-dihydro-5,10-epoxy-S-[3-(N-ethyl-N-methylamino) -propyl] -1 1-keto-5H-dibenzo [a,d] cycloheptene 10,11-dihydro-5-(3-dimethylaminopropyl)-5,10-epoxy-11- keto 3 (7) -methylsulfonyl-5H-dibenzo [a,d] cycloheptene 3 (7 -chloro-1 0,11-dihydro-5-(3-dimethylaminopropyD- 5,10-epoxy-1 l-keto-SH-dibenzo [a,d] cycloheptene 10,11-dihydro-5-(3-dirnethylaminopropyl)-3 (7) -dimethylsulfamoyl-5,10-epoxy-1 1-keto-5H-dibenzo-[a,d] cycloheptene EXAMPLE 32 spiro[10,11-dihydro 5-'(3-dirnethylaminopropyl) 5,10-

epoxy-SH-dibenzo[a,d]cycloheptene]-11,2-m-dithiane A solution of 10,1l-dihydro-S-(3-dimethylaminopropyl) 5,10-epoxy 1l-keto-SH-dibenzo[a,dJcycloheptene (900 mg, 0.003 mole) and 1 ml. of trimethylene dithiol in 20 ml. of glacial acetic acid is stirred and treated with 2 ml. of redistilled boron trifiuoride etherate. After stirring 1% hours at room temperature, the clear yellow solution is allowed to stand overnight. The solution then is poured into 300 m1. of ice-cold 5% aqueous sodium hydroxide. The precipitate is collected, washed with water, air-dried and dissolved in 150 ml. of absolute ether. After removing the insoluble material by filtration, the ether is distilled under reduced pressure. The White crystalline solid residue weighs 1.1 g. (92.5%), MP. 122126 C. The pure product melts at 130.5-132 C. after repeated crystallizations from mixtures of ethanol and water and from isopropyl alcohol.

Analysis.Calcd for C H NOS C, 69.47; H, 6.85; N, 3.52. Found: C, 69.19; H, 6.82; N, 3.40.

EXAMPLE 33 Following the procedure of Example 32, the products enumerated below are obtained employing the products enumerated in Example 31 in place of the ll-keto compound used in Example 32.

spiro[ 10,11-dihydro-5-(3-diethylaminopropyl)-5,10-

epoxy-SH-dibenzo[a,d]cycloheptene]-11,2'-rn-dithiane spiro[10,11oihydro-5,10-epoxy-5-(3-(l-pyrrolidyl)- propyl)-5H-dibenzo[a,d]cycloheptene]-11,2' -mdithiane spiro[10,11-dihydro-5,10-epoxy-5-(3-(1-piperidyl)- propyl)-5H-dibenzo[a,d]cycloheptene]-l1,2' -mdithiane spiro[10,11-dihydro-5,10-epoxy-5-(3-(1-ethyl-4- piperazinyl -propyl 5H-dibenzo a,d] cycloheptene] l 1,2-m-dithiane spiro[10,1l-dihydro-S,10-epoxy-5-(3-(4-morpholinyl)- pro pyl) -5H-dibenzo [a,dJcycloheptene] -1 1,2 -mdithiane spiro[10,11-dihydro-5,10-epoxy-5(3-(N-ethyl-N- methylamino) -propyl) -5H-dibenzo a,d] cycloheptene] 1 1,2'-m-dithiane spiro[10,11-dihydro-5-(3-dimethylaminopropyl)-5,10-

epoxy-3 (7 -methylsulfonyl-SH-dibenzo [a,d] cycloheptene]-11,2'-m-dithiane spiro [3 (7 -chloro-l0, 1 1 -dihydro-5- (3-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo [a,d] cycloheptene] 1 1,2'-m-dithiane spiro[10,1 l-dihydro-S-(3-dimethylaminopropyl)-3 (7 dimethylsulfamoyl-S -epoxy-5H-dibenzo [a,d] cycloheptene]-11,2-m-dithiane EXAMPLE 34 Following the procedure of Example 32, the products enumerated below are obtained employing the compounds enumerated in Example 31 and ethylene dithiol in place of the ll-keto compound and trimethylene dithiol used in Example 32.

spiro[10,1l-dihydro-S-(3-diethylaminopropyl)-5,10- epoxy-5H-dibenzo[a,d]cycloheptene]-11,2-(1',3- dithiolane) spiro[10,1 1-dihydro-5,10-epoxy-5-(3-( 1-pyrrolidy1)- propyl)-5H-dibenzo[a,d]cycloheptene]11,2-(1,3'- dithiolane) spiro 10, 1l-dihydro-S,10-epoxy-5-(3-(1-piperidyl)- propyl)-5H-dibenzo[a,d]cycloheptene]-11,2-(1,3'- dithiolane spiro[ 10,11-dihydro-5,10-epoxy-5-(3-( 1-ethyl-4- piperazinyl) -propyl -5H-dibenzo a,d] cycloheptene] 11,2-(1',3'-dithiolane) spiro[10,1l-dihydro-S,10-epoxy-5-(3-(4-morpholinyl) propyl)-5H-dibenzo[a,d]cycloheptene]-11,2-(1,3 dithiolane) spiro[10,1l-dihydro-S,10-ep0xy-5-(3-(N-ethyl-N- methylamino -propyl -5H-dibenzo [a,d] cycloheptene] 11,2-(1',3-dithiolane) spiro[10,1l-dihydro-S-(3-dimethylaminopropyl)5,10 epoxy-3 (7 )-methylsulfonyl-SH-dibenzo [a,d] cycloheptene]-11,2'-(1,3'-dithiolane) spiro [3 (7) -chloro-10, 1 l-dihydro-S- 3-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo [a,d]cycloheptene]- 11,2'-(1,3-dithiolane) spiro[10,1l-dihydro-5-(3-dimethylarninopropyl)-3(7)- dimethylsulfamoyl-S,10-epoxy-5H-dibenzo [a,d]cycloheptene]-11,2'-(1',3-dithiolane) EXAMPLE 35 10,11-dihydro-5-(3-dimethylaminopropyl)-5,IO-epoxy- SH-dibenzo[a,d1cycloheptene A solution of spiro[10,1l-dihydro-S-(3-dimethylaminopropyl)-5,IO-epoxy-SH-dibenzo[a,d]-cycloheptene] l1, 2'-m-dithiane (600 mg., 0.0015 mole) in 75 ml. of absolute ethanol is stirred and heated to refluxing with 7 g. of Raney nickel for 24 hours. The nickel is removed by filtration through a mat of diatomaceous earth and Washed with absolute ethanol. The alcoholic filtrate is evaporated under reduced pressure, the residual oil dissolved in benzene and the solution again evaporated under reduced pressure, leaving the product as a colorless oily residue weighing 200 mg.

The base may be converted to the hydrogen maleate salt by treating an ethanolic solution with a solution of maleic acid (10% excess) in absolute ether. Further dilution with absolute ether precipitates 10,11-dihydro- 5-(3-dimethylaminopropyl) 5,10 epoxy-SH-dibenzo- [a,d]cycloheptene hydrogen maleate as a white crystalline solid, M.P. l38 C. An analytical sample melts at 141.5143.5 C. after repeated crystallizations from mixtures of isopropyl alcohol and absolute ether.

Analysis.Calcd for C H NO-C H O C, 70.41; H, 6.65; N, 3.42. Found: C, 70.61; H, 6.75; N, 3.45.

EXAMPLE 3 6 Following the procedure of Example 35, the products enumerated below are obtained employing the products enumerated in Examples 33 and 34 in place of the dithiane used in Example 35.

10,1 1-dihydro-5-(S-diethylaminopropyl)-5,10-epoxy- SH-dibenzo [a,d] cycloheptene 10,1l-dihydro-S,10-epoxy-5-[3-(1-pyrrolidyl)-propyl]- SH-dibenzo [a,d] cycloheptene 10,11-dihydro-5,10-epoxy-5-[3-(1-piperidyl)-propyl]- SH-dibenzo a,d] cycloheptene 10,1 l-dihydro-S lO-epoxy-S- 3-( 1-ethyl-4-piperazinyl) propyl] -5H-dibenzo [a,d] cycloheptene 10,1 1-dihydro-5,10-epoxy-5-[3-(4-morpholinyl)-propyl]- SH-dibenzo [a,d] cycloheptene 10,1l-dihydro5,l0-epoxy-5-[3-(N-ethyl-N-methylamino).

propyl] -5H-dibenzo [a,d] cycloheptene 10,1l-dihydro-S-(3-dimethylaminopropyl)-5,10-epoxy- 3 (7 -methylsulfonyl-SH-dibenzo a,d] cycloheptene 3 (7 )-chloro10, 1 1-dihydro-5-( 3 -dimethylaminopropyl) 5,10-epoxy-5H-dibenzo [a,d]cycloheptene 10,11-dihydro-5-(3-dimethylaminopropyl)-3 (7)-dimethylsulfamoyl-S,10-epoxy-5H-dibenzo[a,d] cycloheptene EXAMPLE 37 Trans 10,11 dihydro 5 (3-dimethylaminopropyl)-5,10- epoxy-l 1-hexanoyloxy-5H-dibenzo[a,d]cycloheptene A solution of trans 10,1l-dihydro-5-(3-dimethylaminopropyl) 5,10 epoxy-11-hydroxy-5H-dibenzo[a,d]cycloheptene, 310 mg. (0.001 mole), in 2 ml. of hexanoic anhydride is heated on the steam-bath for 18 hours. The solution is stirred with 75 ml. of water for 4 hours, then cooled in ice and made strongly basic with aqueous sodium hydroxide. The oily base is extracted into benzene and isolated by evaporation of the washed and dried benzene extract under reduced pressure. The residual oil is dissolved in absolute ether and treated with a excess of maleic acid in absolute ethanol. The crystalline hydrogen maleate salt, M.P. 108-1 10 C., is obtained in a yield of 350 mg. (67%). Recrystallizations from ethanolether and isopropyl alcohol-ether afford an analytical sample, M.P. 109110 C.

Analysis.Calcd fOI' c25H33NO3C4H O Z C, H, 7.12; N, 2.68. Found: C, 68.61; H, 7.07; N, 2.62.

EXAMPLE 3 8 10,11-dihydro-5-(3-dimethylaminopropyl)-5,10-epoxy-11- hydroxyimino-SH-dibenzo[a,d]cycloheptene 10,11 dihydro-5-(3-dimethylaminopropyl)-5,l0-epoxy- 1l-keto-5H-dibenzo[a,d]cycloheptene, 310 mg. (0.001 mole), together with 80 mg. (0.00115 mole) of hydroxyamine hydrochloride, 100 mg. (0.0012 mole) of sodium acetate, 1 ml. of water, and 9 ml. of methanol is heated to refluxing for 2 hours. Methanol is distilled under reduced pressure and the residue dissolved in water. The solution is rendered alkaline and the precipitate collected, washed with water, and dried in vacuo. The yield of product, M.P. 197-204 C., is 300 mg. (93%). A sample purified by repeated crystallizations from 95% ethanol melts at 206-210 C.

Analysis.Calcd for C H N O Q74. 51; H, 6.88; N, 6.89. Found: C, 74.37; H, 7.12; N, 8.56.

EXAMPLE 39 11-amino-10,11-dihydro-5-(3-dimethylaminopropyl)-5,10- epoxy-SH-dibenzo[a,d]cycloheptene 10,11 dihydro-5-(3-dimethylaminopropyl)-5,IO-epoxy- 11-hydroxyimino-5H-dibenzo[a,d]cycloheptene, 400 mg. (0.00124 mole), is dissolved in 18 ml. of hot absolute ethanol and the solution is concentrated -by distillation of 12 ml. of ethanol. To the refluxing mixture, sodium spheres, 460 mg. (0.02 g., atom), are added as rapidly as possible over a 4 minute period. After another 15 minutes at reflux, 2 ml. of absolute ethanol are added and refluxing is continued until dissolution of the sodium is complete. The cooled mixture is diluted with an equal volume of water and ethanol is evaporated under reduced pressure. The oily product that separates from the residue is extracted into benzene. After Washing with water, the benzene extract is evaporated to dryness under reduced pressure, leaving the oily base as the residue in a yield of 275 mg. (72%).

The base may be converted to the dihydrogen maleate salt by treating an ethanolic solution with two equivalents of maleic acid dissolved in absolute ethanol. Dilution with absolute ether precipitates 11-amino-10,11-dihydro-5-(3- dimethylaminopropyl) 5,10-epoxy-5H-dibenzo[a,d]cycloheptene dihydrogen dimaleate that melts at 163167 C., dec., after recrystallization from a mixture of absolute ethanol and absolute ether. Further purification affords a Sample melting at 169-172 C., dec.

28 Analysis.-Calcd for C H N O-2C H O C, 62.21; H, 5.97; N, 5.18. Found: C, 61.90; H, 6.33; N, 5.46.

EXAMPLE 40 10,1 l-dihydro-l 1-dimethylamino-5-(3 -dimethylaminopropyD-S,lO-epoxy-5H-dibenzo[a,d]cycloheptene A mixture of 11-amino-10,1l-dihydro-5-(3-dimethylaminopropyl) 5,10-epoxy-SH-dibenzo[a,d]cycloheptene, 308 mg. (0.001 mole), 37% formaldehyde, mg. (0.0022 mole, and 98100% formic acid, 250 mg. (0.005 mole), is heated on a steam-bath for 8 hours. The solution is cooled, diluted with 10 ml. of 6 N hydrochloric acid and the excess formic acid and formaldehyde removed by distillation under reduced pressure. The 10,11-dihydro-1ldimethylamino 5 (3-dimethylaminopropyl)-5,l0-epoxy- S-H-dibenzo[a,d]cycloheptene is obtained when the resid ual aqueous acid solution is rendered alkaline.

EXAMPLE 41 Trans 10,11 dihydro l1-dimethylamino-5-(3-dimethylaminopropyD-S, l 0-ep oxy-5Hdibenzo[a,d]cycloheptene A solution of trans 11-amino-10,11-dihydro-5-(3-dimethylaminopropyl) 5,10 epoxy-5H-dibenzo[a,d]cycloheptene, 310 mg. (0.001 mole), in 2 ml. of 98-100% formic acid and 0.2 ml. of 37% aqueous formaldehyde is allowed to stand at room temperature for 16 hours and then heated on the steam-bath for 4 hours. Solvents are distilled under reduced pressure and the residual syrup is dissolved in 10 ml. of water. The solution is rendered strongly alkaline and the oily base that separates is extracted into benzene. After washing and drying the combined extracts, benzene is evparoated under reduced pressure leaving the product as a colorless oil weighing 280 mg. The base is converted to the dihydrogen dimaleate by treating a solution in absolute ethanol with two equivalents of maleic acid dissolved in absolute ethanol. Dilution to incipient crystallization with ether precipitates the dihydrogen dimaleate, M.P. 151-l53 C., dec., in a yield of 400 mg. Recrystallization from isopropyl alcohol gives product, M.P. 150.5l51.5 C.

AnalysisCalcd for C22H28N2O2C4H4O4: C, 63.37; H, 6.38; N, 4.93. Found: C, 63.56; H, 6.54; N, 4.96.

EXAMPLE 42 11-acetamido-10,11-dihydro-5-(3-dimethylaminopropyl)- 5 10-ep oxy- 5H-dib enzo [a,d] cycloheptene EXAMPLE 43 Trans 11 acetamido-l0,1 1dihydro-5-(Ii-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo [a,d] cycloheptene A solution of trans 1l-amino-10,l1-dihydro-5-(3-dimethylaminopropyl) 5,10-epoXy-5H-dibenzo [a,d]cyclo heptene, 500 mg. (0.00162 mole), and acetic anhydride, 0.17 g. (0.00162 mole) in 15 ml. of dry acetone is allowed to stand at room temperature for 5 days. Solvent is distilled under reduced pressure and the residual syrup is dissolved in water. The solution is rendered alkaline with concentrated ammonium hydroxide and the oily base that separates is extracted into chloroform. After washing and drying the combined extracts, chloroform is distilled under reduced pressure leaving the product as a yellow glass. Trituration with absolute ether gives crystalline product, M.P. 173l77 C., in a yield of 200 mg. Repeated recrystallizations from acetonitrile raise the melting point to 179-181 C.

29 Analysis.Calcd for C H N O C, 75,38; H, 7.48. Found: C, 75.30; H, 7.75.

EXAMPLE 44 Following the procedure of Example 42, the products enumerated below are obtained employing the anhydride designated below in place of the acetic anhydride used in Example 42.

Anhydride Product 30 EXAMPLE 49 11 amino [3 (N-carbethoxy-N-methylamino) propyl] 10,11 dihydro 5,10 epoxy 5H dibenzo [a,d] cycloheptene The oxime obtained in Example 48, 385 mg. (0.001 mole), is dissolved in 6 ml. of hot absolute ethanol. To the refluxing mixture, sodium spheres, 460 mg. (0.02 g., atom), are added as rapidly as possible. After another 15 minutes at reflux, 2 ml. of absolute ethanol are added 10 and refluxing is continued until dissolution of the so- Pmpwmc anhydnde" dium is complete. The cooled mixture is diluted with an hepteneequal volume of Water and ethanol is evaporated under u y e y y m -d hy -ffl y reduced pressure. The residual mixture is extracted with amimPwPYl)'5IHPMY'5HdDeHZMam benzene and the product obtained by evaporation of the cycloheptene.

washed and dried benzene extract. A solution of 1l-acetamido-10,1 1-dihydro-5-(3-di- EXAMPLE 5 gi g s g g is: 2 2: gggg ffa fi g g g gi g 5 [3 (N carbethoxy-N-methylamino)-propyl]-10,l1- ether is added dropwise to a stirred suspension of 85 mg. dlhgdro I L dlmethylammo 5a1O'ePOXY'SH'dIbc1120 (0.0022 mole) of lithium aluminum hydride in 5 ml. of 1cyc 0 ep ene absolute ether at room temperature and in an atmosphere 11 amino 5 [3-(N-carbethoxy-N-methylamino)- of nitrogen. After stirring at refluX for 6 h the propyl] 10,11 dihydro 5,10-epoxy-5H-dibenzo[a,d] t i cooled in ice and hydrolyzed by the successi cycloheptene, 365 mg. (0.001 mole), 37% formaldehyde, dropwise addition of 0.1 ml. of water, 0.1 ml. of 20% 80 mg. (0.0022 mole), and 98-100% formic acid, 250 aqueous sodium hydroxide and 0.3 ml. of water. The mg. (0.005 mole), are heated on a steam-bath for 8 ether solution is filt m the granular p pitate, hours. After cooling, the solution is diluted with 10 washed with water, and dried over anhydrous sodium ml. of 6 N hydrochloric acid and the excess formic sulfate. Evaporation of the ether leaves 10,11-dihydro-5- acid and formaldehyde removed by distillation under (3 dimethylaminopropyl) ll-ethylamino-5,l0-epoxy- 3O reduced pressure. The product is obtained when the 5H-dibenzo[a,d]cycloheptene as the residue. residual aqueous acid solution is rendered alkaline.

EXAMPLE 46 EXAMPLE 51 am 1 5, h roducts 10,11 dihydro 11 dimethylamino-S,l0-epoxy-5-(3- missin bazt zzz satstamptsytg t: 2...... cycloheptene designated below in place of the 11- A solution of 5-[3-(N-carbethoxy-N-methylamino)- acetamido 10,11 dihydro-5-(3-dimethylaminopropyl)- propyl] 10,11 dihydro 1l-dimethylamino-S,10-epoxy- 5,10-epoxy-5H-dibenzo[a,d1cycloheptene used in Ex- SH-dibenzo[a,dJcycloheptene, 395 mg. (0.001 mole), and ample 45. 0 potassium hydroxide, 300 mg. (0.00535 mole), in 6 ml.

Product 10,11-dihydro-5-(3-dimethylaminopropyl) -5,10 epoxw-11- propionamido-5H-dibenzo[a,d]cycloheptene.

ll-butyramido-IO 11-dihydro-5-(B-dimethylarninopropyl) -5,10-epoxy- 5H-dibenzoia,dicycloheptene.

EXAMPLE 47 5 [3-(N-carbethoxy N methylamino)-propyl]-10,11- dihydro 5,10 epoxy-11-keto-5H-dibenzo[a,d]cycloheptene A solution of 10,11 dihydro-S- (3-dimethylaminopropyl) 5,10 epoxy 11-keto-SH-dibenzo[a,d]cycloheptene, 620 mg. (0.002 mole), in 3 ml. of dry benzene is added dropwise to a stirred solution of 1.0 ml. of ethyl chloroformate in 3 ml. of dry benzene. After stirring for 1 hour at reflux, the mixture is cooled, diluted with benzene, and washed with 2 N hydrochloric acid, then with water. Evaporation of the benzene under reduced pressure leaves the product as the residue.

EXAMPLE 48 5 [3 (N carbethoxy-N-methylamino)-propyl]-10,ll-

dihydro-5,l0-epoxy 11 hydroxyimino SH-dibenzo [a,d]cycloheptene 5 [3 (N-carbethoxy-N-methylamino)-propyl]-10,1ldihydro 5,10 epoxy 11 keto 5H dibenzo[a,d] cycloheptene, 370 mg. (0.001 mole), together with 80 mg. (0.00115 mole) of hydroxylamine hydrochloride, 100 mg. (0.0012 mole) of sodium acetate, 1 ml. of water and 9 ml. of methanol, is heated to refluxing for 2 hours. Methanol is distilled under reduced pressure and the residue triturated with water. The product is obtained as the precipitate.

l0,11-dihydro-5(d dimethylaminopropyl) 5,l0epoxy-11- 11-buty1amino-10,11-dihydro-5-(3-dimethylaminopropyl)- 5,10-ep0xy-5H-dibenzo[a,d]cycloheptene.

of n-butyl alcohol is stirred and heated to refluxing in a nitrogen atmosphere for 8 hours. The solvent is evaporated under reduced pressure and the residue partitioned between benzene and water. Evaporation of the washed and dried benzene extract leaves the product as the residue.

EXAMPLE 52 1 0,1 l-dihydro-S- 3-dimethylaminopropyl) -5, l0-epoxy- 1 l-hydroxy- 1 l-methyl-SH-dibenzo [a,d] cycloheptene Magnesium tumings, mg. (0.06 g., atom), a crystal of iodine, and 25 m1. of tetrahydrofuran are placed in a 50 ml. reaction flask fitted with a stirrer, reflux condenser and gas inlet tube. The apparatus is flushed with dry nitrogen and protected from atmospheric moisture by means of a drying tube. The reaction is initiated with a drop of methyl iodide and then methyl chloride is introduced below the surface of the stirred mixture at room temperature. Passage of the gas is continued until all of the magnesium dissolves. The solution of the Grignard reagent then is added dropwise to a stirred solution of 900 mg. (0.0029 mole) of 10,11- dihydro 5-(3-dimethylaminopropyl)-5,1'0-epoxy-ll-keto- SH-dibenzo[a,d]-cycloheptene in 25 ml. of tetrahydrofuran maintained in a nitrogen atmosphere and cooled in an ice-bath. The mixture is stirred at room temperature for 45 minutes and the bulk of the tetrahydrofuran is evaporated below 50 C. under reduced pressure. The

residue is dissolved in benzene and hydrolyzed by the dropwise addition of 10 ml. of water. The benzene layer is separated by decantation and the gelatinous precipitate washed with several portions of benzene. After washing with Water, the conbined benzene solutions are extracted with three 25 ml. portions of 0.5 M citric acid. The acid extract is rendered alkaline and the oily base extracted into benzene. The Washed and dried benzene extract is evaporated under reduced pressure, leaving the product as an oily residue that solidifies on trituration with absolute ether. The yield of product melting at 108110 C. is 700 mg. (75%). The base may be converted to the hydrogen maleate salt by treating an ethanolic solution with a 10% excess of maleic acid dissolved in absolute ethanol. Dilution with absolute ether precipitates 10,1l-dihydro-S-(3-dimethylaminopropyl) 5,10-epoxy-11-hydroxy-l1-methyl5H-dibenzo[a,d] cycloheptene hydrogen maleate, M.P. 182184 C. The melting point is unchanged by further recrystallization.

Analysis.Cald for C21H25NO2C4H4O4: C, H, 6.65; N, 3.19. Found: C, 67.89; H, 6.62; N, 3.30.

EXAMPLE 53 10,1 l-dihydro-5-(3-dimethylaminopropyl)-5,10-epoxy- 1l-methoxyimino-5H-dibenzo [a,d] cycloheptene 10,11 dihydro 5 (3 dimethylaminopropyl)-5,lepoxy 11 keto-H-dibenzo[a,d]cycloheptene, 1.5 g. (0.005 mole), together with 500 mg. (0.006 mole) of methoxyamine hydrochloride, 825 mg. (0.0061 mole) of sodium acetate trihydrate, 5 ml. of water, and 45 ml. of methanol is heated to refluxing for 19 hours. Methanol is distilled under reduced pressure and the residue dissolved in water. The solution is rendered alkaline and the oily base that separates is extracted into benzene. After washing and drying the combined extracts, benzene is evaporated under reduced pressure leaving the product as an oil Weighing 1.55 g. A sample of the base from a previous experiment is converted to the hydrogen oxalate salt by treating an ethanolic solution with one equivalent of oxalic acid dissolved in absolute ethanol. Dilution with ether precipitates 10,11-dihydro-5-(3-dimethylaminopropyl) 5,10 epoxy 11 methoxyimino- 5H dibenzo[a,d]cycloheptene hydrogen oxalate as a white crystalline solid, M.P. dec. 159.5-1605" C. Repeated recrystallizations from absolute ethanol give product, M.P. dec. 162.5163.5 C.

AnalysiS.Cald for C21H24N202'C2H2041 C, H, 6.15; N, 6.57. Found: C, 64.75; H, 6.11; N, 6.57.

EXAMPLE 54 1 1-acetoxyimino-10,l 1-dihydro-5- 3-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo[a,d]cycloheptene A solution of 10,1l-dihydro-S-(3-dimethylamin0-propyl) 5,10 epoxy 11 hydroxyimino-SH-dibenzo [a,d] cycloheptene, 645 mg. (0.002 mole), in 4 ml. of acetic anhydride is heated on the steam-bath for 1 /2 hours and then allowed to stand at room temperature for 2 days. Solvent is distilled under reduced pressure and the residual syrup dissolved in ml. of Water. After repeated extraction with benzene, the aqueous solution is cooled in ice, rendered strongly alkaline, and the oily base that separates is extracted into benzene. After washing and drying the combined extracts, benzene is evaporated under reduced pressure, leaving the product as an oily solid weighing 650 mg. Recrystallization from etherpetroleum ether gives product, M.P. 129132 C., and further recrystallizations from ether-petroleum ether raise the melting point to 133134 C.

Analysis.-Cald for C H N O C, H, N, 7.69. Found: C, 72.31; H, 6.81; N, 7.64.

EXAMPLE 55 Trans 10,11 dihydro-S-(B-dimethylaminopropyl)-5,10- epoxy 11-methanesulfonamido-SH-dibenzo[a,d] cycloheptene Trans 11 amino-10,11dihydro-5-(3-dimethylaminopropyl) 5,l0-epoxy-5H-dibenzo[a,d]cycloheptene, 308 mg. (0.001 mole), and 2 ml. of dry pyridine are stirred and cooled in an ice-bath. Methanesulfonyl chloride, 0.1 ml., is added dropwise. Stirring is continued for 5 hours at room temperature and for 5 minutes on the steam-bath and the solution then is poured into 40 ml. of water. The aqueous solution is adjusted to pH 8 with 5% aqueous sodium hydroxide and the precipitate is collected, washed with Water, and dried in a vacuum oven at 60. The product, M.P. 207-210 C., weighs 275 mg. Repeated recrystallizations from ethanol raise the melting point to 2l0211 C.

Analysis.-Cald for C H N O S: C, 65.26; H, 6.78; N, 7.25. Found: C, 65.17; H, 6.95; N, 7.06.

EXAMPLE 56 Trans 1 1-amino-10,11-dihydro-5,10-epoxy-5-(3-methylaminopropyl)-SH-dibenzo[ a,d cycloheptene A solution of 10,1l-dihydro-S,10-epoxy-5-(3-methylaminopropyl) 11-hydroxyimino-5H-dibenzo[a,d]cycloheptene, 650 mg. (0.0021 mole), in 50 ml. absolute methanol-5 ml. concentrated amonium hydroxide is shaken with hydrogen at atmospheric pressure in the presence of 300 mg. of 5% paladium on charcoal until the uptake of hydrogen is complete. The mixture is filtered through a mat of diatomaceous earth and the filtrate evaporated to dryness under reduced pressure. The residual yellow oily base weighs 600 mg. and is converted to the dihydrogen dimaleate by treating a solution of the base in isopropyl alcohol with two equivalents of maleic acid dissolved in isopropyl alcohol. The dihydrogen dimaleate is obtained as white crystals, M.P. 173175 C. in a yield of 800 mg. Repeated recrystallizations from isopropyl alcohol give product, M.P. 187188 C.

Analysis.Calcd for C19H22N2O2'c4H O4: C, H, 5.74; N, 5.32. Found: C, 61.86; H, 6.07; N, 5.07.

EXAMPLE 57 10,11-dihydro-5,10epoxy-11-hydroxyimino-5-(3-methylaminopropyl)-SH-dibenzo[a,d]cycloheptene By replacing the 10,1l-dihydro-S-(3-dimethylaminopropyl) 5,10 epoxy 11 keto-SH-dibenzo[a,d]cycloheptene used in Example 38 with an equimolecular amount of 10,11-dihydro-5,10-epoxy-11-keto-5-(3-methylaminopropyl)5H-dibenzo[a,d]cycloheptene and following substantially the same procedure described in Example 38, there is obtained 10,11-dihydro-5,10-epoxy-11- hydroxyimino 5 (3-methy-laminopropyl)-5H-dibenzo- [a,d]cycloheptene. The yield of white crystalline base, M.P. 210214 C. dec., is 36%. Recrystallizations from absolute ethanol raise the melting point to 2l4216 C. dec.

Analysis.Calcd for C H N O C, 74.00; H, 6.54; N, 9.09. Found: C, 73.78; H, 6.42; N, 8.84.

EXAMPLE 58 10,11-dihydro-5,10-epoxy-11-keto-5-(3-methylaminopropyl)-SH-dibenzo a,d] cycloheptene By replacing the trans 10,11-dihydr0-5-(3-dimethylaminopropyl) 5,10-epoxy-1l-hydroxy-SH-dibenzo[a,d]- cycloheptene used in Example 30 with an equimolecular amount of trans 10,11-dihydro-5,10-epoxy-ll-hydroxy-S- (3 methylaminopropyl) 5H-dibenzo[a,d]cycloheptene and following substantially the same procedure described in Example 30, there is obtained 10,11-dihydro-5,10- epoxy 11 keto-5-(3-methylaminopropyl)-5H-dibenzo- [a,d]cycloheptene. The yield of yellow oily base is quantitative. The base is converted to the hydrogen maleate by dissolving it in absolute ethanol and adding a solution of a slight excess of maleic acid in absolute ethanol. Dilution to incipient crystallization with absolute ether precipitates the hydrogen maleate, M.P. ISO-151 C. in a yield of 67%. The melting point is unchanged by recrystallization from absolute ethanol-absolute ether.

33 Analysis.-Calcd for C H NO -C H O C, 67.46; H, 5.66; N, 3.42. Found: C, 67.07; H, 5.70; N, 3.48.

EXAMPLE 59 Trans 11 acetoxy 10,1l-dihydro-S-(3-methylaminopropyl) -5,10-epoxy-5H-dibenzo [ad] cycloheptene A solution of trans 10,11-dihydro-5,10-epoxy-1lhydroxy 5 (3 methylaminopropyl)-5H-dibenzo[a,d] cycloheptene hydrogen maleate, 1.0 g. (0.00243 mole) in 5 ml. of glacial acetic acid-5 ml. of 6 N hydrochloric acid is stirred and cooled in an ice-salt bath. Acetyl chloride, 50 ml. is added rapidly dropwise. Stirring is continued for 1 hour in the cold and the solution then is concentrated below 25 to a volume of 15-20 ml. under reduced pressure. Dilution of the residual solution with 50 ml. of absolute ether precipitates the product hydrochloride, M.P. 247249 C. dec., in a yield of 850 mg. Repeated recrystallizations from absolute ethanol give product, M.P. 254255 C. dec.

Analysis.-Calcd for C H NO -HCl: C, 67.47; H, 6.47; N, 3.75. Found: C, 67.70; H, 6.79; N, 3.90.

EXAMPLE 60 Trans 1 l-benzoyloxy-10,11-dihydro-5-(3-dimethylaminopropyl)-5,10epoxy-5H-dibenzo[a,d1cycloheptene Trans 10,1 1-dihydro-5-(3-dimethylaminopropyl)-5,10- epoxy-1 1-hydroxy-5H-dibenzo[ a,d] cycloheptene, 618 mg. (0.002 mole), and 3 m1. of dry pyridine are stirred and cooled in an ice-bath. Benzoyl chloride, 310 mg. (0.0022 mole) is added dropwise. Stirring is continued for 1 hour in the cold and the mixture then is allowed to stand 24 hours at room temperature. After heating for 45 minutes on the steam bath, the mixture is poured into 50 ml. of water. This solution is cooled in an ice-bath, rendered strongly alkaline, and the oily base that separates is extracted into benzene. After washing the combined extracts with Water, the benzene is evaporated leaving the product as a yellow oil in a yield of 800 mg. The base is converted to the hydrochloride by dissolving it in 5 ml. of absolute ethanol and adding 0.35 ml. of 5.92 N ethanolic hydrogen chloride. Dilution to incipient crystallization with 25 ml. of absolute ether precipitates trans 11 benzoyloxy 10,11 dihydro-5-(3-dimethylaminopropyl) 5,10-epoxy-5H-dibenzo[a,d]cycloheptene hydrochloride, M.P. 253-255 C. dec., in a yield of 790 mg. Recrystallizations from isopropyl alcohol and from absolule alcohol-absolute ether raise the melting point to 259.5-260.5 C. dec.

Analysis.Calcd for C H NO -HCI: C, 72.06; H, 6.27; N, 3.11. Found: C, 71.86; H, 6.64; N, 2.89.

EXAMPLE 61 Trans 10,11 dihydro 5 (3 dimethylaminopropyl)- 5,10 epoxy 11 hydroxy 5H dibenzo[a,d]cycloheptene N-oxide Trans 10,11 dihydro 5 (3 dimethylaminopropyl)- 5,10 epoxy l1 hydroxy 5H dibenzo[a,d]cycloheptene, 2.06 g. (0.0067 mole), and 20 ml. of absolute methanol are stirred and cooled in an ice-bath. Hydrogen peroxide, 2.3 g. of 30%, is added dropwise. Stirring is continued for 1 hour in the cold and for 19 hours at room temperature and the mixture then is allowed to stand for 24 hours at room temperature. After cooling in an icebath, the mixture is treated with a suspension of 100 mg. of 5% palladium on charcoal in 1 ml. of water and stirred at room temperature for 2 /2 hours when a test for peroxide is negative. After filtration through a mat of diatomaceous earth, the filtrate is evaporated below 40 C. under reduced pressure. The residual colorless glass weighs 2.3 g. after drying for 3 days in a vacuum desiccator over phosphorus pentoxide. The base is converted to the hydrogen maleate by dissolving it in 20 m1. of cold absolute ethanol and adding a solution of 860 mg. of maleic acid in 5 ml. of absolute ethanol. Dilution to incipient crystallization with 25 ml. of absolute ether precipitates the hydrogen maleate, M.P. 151-152 C. dec., in a yield of 2.6 g. Recrystallization from cold absolute methanol-absolute ether gives product, M.P. 155156 C. dec.

Analysis.'Calcd for CZOHZ3NO3'C4H4O4: C, H, 6.16; N, 3.17. Found: C, 65.37; H, 6.16; N, 3.13.

EXAMPLE 62 Trans 10,11 dihydro 5 [3 N carbethoxy N- methylamino)propyl] 5,10 epoxy 11 hyd-roxy- 5 H-dibenzo [a,d] cycloheptene Trans 10,1 dihydro 5 (3 dimethylaminopropyl)- 5,10 epoxy l1 hydroxy 5H dibenzo[a,d]cycloheptene, 3.1 g. (0.01 mole), is added in portions over 30 minutes with stirring to ml. of ethyl chloroformate. The mixture is stirred and heated to refluxing for 30 hours until a clear solution is obtained. Solvent is distilled under reduced pressure and the residual oil dissolved in benzene. The benzene solution is washed with water, 0.5 M citric acid, and water, dried by filtration through anhydrous sodium sulfate, and evaporated under reduced pressure. The trans 10,11 dihydro 5 [3-(N-carbethoxy-N- methylamino)propyl] 5,10 epoxy 11 hydroxy 5H- dibenzo[a,d]cycloheptene is obtained as a viscous, yellow oil weighing 3.6 g.

EXAMPLE 63 Trans 10,11 dihydro 5,10 epoxy ll hydroxy 5- (3 methylaminopropyl) 5H dibenzo[a,d]cycloheptene Trans 10.11 dihydro 5 [3 (N carbethoxy N- methylamino)propyl] 5,10 epoxy 11 hydroxy 5H- dibenzo[a,d]cycloheptene, 2.76 g. (0.0075 mole), and 10 g. (0.175 mole) of potassium hydroxide are stirred and heated to refluxing in 50 ml. of n-butyl alcohol for 16 hours. Solvent is distilled under reduced pressure and the residue partitioned between benzene and water. The combined benzene extracts are washed with water and extracted with 0.5 M citric acid. The aqueous acid solution is rendered strongly alkaline and the oily base that separates is extracted into benzene. Evaporation of the washed and dried benzene extract leaves the crude product as a yellow oil Weighing 1.2 g. The base is converted to the hydrogen maleate by treating a solution in isopropyl alcohol with a solution of 520 mg. of maleic acid in isopropyl alcohol. Dilution to incipient crystallization with absolute ether precipitates the hydrogen maleate, M.P. -138 C., in a yield of 1.3 g. Recrystallization from isopropyl alcohol-absolute ether gives product M.P. 152-154 C.

Analysis.'Calcd for C19H21NO2'C4H404: C, H, 6.12; N, 3.40. Found: C, 66.88; H, 6.40; N, 3.60.

EXAMPLE 64 10,1l-dihydro-5-(3-dimethylan'1inopropyl)-5,IO-epoxy- 1 l-hydrazono-SH-dibenzo [a,d] cycloheptene 10,11 dihydro 5 (3 dimethylaminopropyl) 5,10- epoxy 11 keto 5H dibenzo[a,d]cycloheptene, 620 mg. (0.002 mole), together with 0.5 ml. of 64% hydrazine, 2 ml. of triethylamine, and 6 ml. of absolute ethanol is heated to refluxing for 2 /2 hours. The cooled solution is diluted with water and the oily base extracted into benzene. The washed benzene extract is evaporated under reduced pressure, leaving the oily base as the residue in a yield of 500 mg. Trituration with absolute ether gives the product as an oily solid, M.P. dec. 100-120 C. Repeated recrystallizations from cyclohexane 'afiord an analytical sample, M.P. dec. l3l-133 C.

Analysis.-Calcd for C H N O: C, 74.74; H, 7.21; N, 13.07. Found: C, 74.65; H, 7.42; N, 12.91.

35 EXAMPLE 65 11 acetoxy 10,11 dihydro 5 (3 dimethylaminopropyl) 5,10 epoxy 11 methyl 5H dibenzo [a,d] cycloheptene By replacing the cis 10,11 dihydro 5 (3 dimethylaminopropyl) 5,10 epoxy 11 hydroxy SH-dibenzo [a,d]cycloheptene used in Example 14 with an equimolecular amount of 10,11 dihydro 5 (3 dimethylaminopropyl) 5,10 epoxy l1 hydroxy 11 methyl-5H dibenzo[a,d]cycloheptene and following substantially the same procedure descirbed in Example 14, there is obtained 11 acetoxy 10,11 dihydro 5 (3 dimethylaminopropyl) 5,10 epoxy 11 methyl 5H dibenzo [a,d]cycloheptene. The yield of white crystalline base,

M.P. 108122 C., is 49%. An analytical sample melts at 122-126 C. after recrystallization from a mixture of ether and petroleum ether and sublimation at 115 C.

and 0.05 mm.

Analysis.Calcd for C H NO C, 75.59; H, 7.45;

N, 3.83. Found: C, 75.72; H, 7.45; N, 3.77.

EXAMPLE 66 5 [3 (N carbethoxy N methylamino) propyl]- 10,ll dihydro 5,10 epoxy l1 hydroxy 11- methyl-SH-dibenzo [a,d cycloheptene By replacing the trans 11 acetoxy 10,11 dihydro- 5 (3 dimethylaminopropyl) 5,10 epoxy 5H dibenzo[a,d]cycloheptene used in Example 25 with an equimolecular amount of 10,11 dihydro 5 (3 dimet-hylaminopropyl) 5,10 epoxy 11 hydroxy 11 methyl- 5H dibenz[a,d]cycloheptene and following substantially the same procedure described in Example 25, there is obtained [3 (N carbethoxy N methylamino) propyl] 10,11 dihydro 5,10 epoxy 11 hydroxyll methyl 5H dibenzo[a,d]cycloheptene. The yield of yellow oily urethane is 95%.

EXAMPLE 67 10,1l-dihydro-5,10-ep0xy-1l-hydroxy-l1-methyl-5-(3- methylaminopropyl -5H-dibenzo [a,d] cycloheptene A solution of 5-[3-(N-carbethoxy-N-methylamino) propyl] 10,11 dihydro 5,10 epoxy 11 hydroxy- 11 methyl 5H dibenzo[a,d]cycloheptene (800 mg., 0.00216 mole) and potassium hydroxide (8.0 g., 0.014 mole) in 40 ml. of n-butyl alcohol is stirred and heated to refluxing in a nitrogen atmosphere for 12 hours. The solvent is evaporated under reduced pressure and the residue partitioned between benzene and water. After reextraction of the aqueous phase, the combined benzene extracts are washed with water and then extracted with three portions of 0.5 M citric acid. The citric acid extract is rendered alkaline with sodium hydroxide and the oily base extracted into benzene. The washed and dried benzene extract is evaporated to dryness under reduced pressure, leaving the crystalline base as the residue in a yield of 400 mg. (60%). Sublimation at 120-128 C. and 0.02 mm. gives an analytical sample, M.P. 156.5158.5 C.

Analysis.Calcd for C H NO C, 77.64; H, 7.49; N, 4.53. Found: C, 77.90; H. 7.36; N, 4.65.

EXAMPLE 68 10,11 dihydro 5 [3 (N carbethoxy N methylamino)propyl] 5,10 epOXy 5H dibenzo[a,d]cycloheptene A solution of 2.1 g. (0.00717 mole) of 10,11-dihydro- 5 (3 dimethylaminopropyl) 5,10 epoxy 5H dibenzo[a,d]cycloheptene in 11.5 ml. of dry benzene is added dropwise to a stirred solution of 3.05 ml. of ethyl chloroformate in 7.6 ml. of dry benzene. An oil separates and the mixture is stirred and heated to refluxing for 16-18 hrs. Benzene is added and the solution is washed with three portions each of water, 0.5 M citric acid, and

water. Distillation of the benzene under reduced pressure 7 leaves the product as the oily residue in a yield of 2.3 g. 91%).

EXAMPLE 69 10,1 1-dihydro-5,10-epoxy-5-(3-methylaminopropyl)-5H- dibenzo [a,d cycloheptene 10,11 dihydro 5 [3 (N carbethoxy N methylamino)propyl] 5,10 epoxy 5H dibenzo[a,d]cycloe heptene, 2.3 g. (0.00655 mole), together with 25g. of potassium hydroxide and ml. of n-butyl alcohol are stirred and heated to refluxing in an atmosphere of nitrogen for 12 hr. Solvent is distilled under reduced pressure and the residue partitioned between benzene and water. The benzene layer is separated, washed with water, and extracted with 0.5 M citric acid. The acid extract is rendered strongly alkaline with sodium hydroxide and the oily base is extracted into benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the oily residue weighing 1.5 g. (82%). The base may be converted to the hydrogen oxalate by treating an ethanolic solution with a 10% excess of oxalic acid in absolute ethanol. The hydrogen oxalate precipitates in white crystals, M.P. 144148 C. Repeated recrystallizations from mixtures of absolute ethanol and absolute ether afford an analytical sample, M.P. 151.5 C.

Analysis.-Calcd for C H NO'C H O C, 68.28; H, 6.28; N, 3.79. Found: C, 68.11; H, 6.41; N, 3.67.

EXAMPLE 70 Trans 10,11-dihydro-5-(3-dimethylaminopropyl)-5, 10-epoxy-1 l-hydroxy-SH-dibenzo[a,d]cyc1oheptene Racemic trans 10,11-dihydro-5-(3-dimethylaminopropyl 5, l0-epoxy-l l-hydroxy-SH-dibenzo [a,d] cycloheptene, 12.36 g. (0.04 mole), is dissolved in 200 ml. of boiling absolute ethanol and treated with a solution of 6.0 g. (0.04 mole) of tartaric acid in 150 ml. of warm absolute ethanol. The tartrate crystallizes as the solution cools and several crops are collected until no further precipitation occurs. The ethanolic mother liquor then is evaporated to dryness under reduced pressure and the residual syrup is dissolved in 100 ml. of water. The

- solution is rendered strongly alkaline with aqueous sodium hydroxide and the oily base extracted into benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the crystalline base weighing 1.52 g. Recrystallization from benzene hexane affords 1.35 g. of product, M.P. 154-157 C.

The base is dissolved in 20 ml. of boiling absolute ethanol and treated with a solution of 655 mg. (0.00437 mole) of tartaric acid in 10 ml. of warm absolute ethanol. The tartrate separates in white crystals, M.P. 237239 C. dec.; yield, 1.40 g. Three recrystallizations from 95% ethanol give product of constant specific rotation;

M.P. 238239 C. dec.

Analysis.-Calcd for C H NO /2C H O C, 68.58; H, 6.82. Found: C, 68.44; H. 6.96.

The tartrate, 700 mg. (0.00182 mole), is dissolved in 20 ml. water, the solution made strongly basic with 5% aqueous sodium hydroxide, and the oily base extracted into benzene. Evaporation of the washed and dried benzene extract'under reduced pressure leaves the crystalline base. Recrystallization from a mixture of benzene and hexane gives 476 mg. of product, M.P. 156- 158 C.,

[ 132 m.. (i t0 0%) Analysis.-Calcd for C H- NO c, 77.64; H, 7.4.9; N, 4.53. Found: C, 77.65; H, 7.39; N, 4.63.

37 EXAMPLE 71 Trans 10,1 l-dihydro-S-(3-dimethylaminopropyl)-5, 10-epoxy-1 l-hydroxy-SH-dibenzo [a,d] cycloheptene Racemic trans 10,11 dihydro (3 dimethylaminopropyl) 5,10 epoxy 11 hydroxy 5H dibenzo[a,d] cycloheptene, 12.36 g. (0.04 mole), is dissolved in 200 ml. of boiling absolute ethanol and treated with a solution of 6.0 g. (0.04 mole) of tartaric acid in 150 ml. of warm absolute ethanol. After the addition of 50 ml. of 95% ethanol, the tartrate crystallizes as the solution cools and is collected after several days at room temperature. The ethanolic mother liquor then is evaporated to dryness under reduced pressure and the residual syrup is dissolved in 100 ml. of water. The solution is rendered strongly alkaline with aqueous sodium hydroxide and the oily base extracted into benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the crystalline base weighing 1.9 g., M.P. 155-157 C.

The base is dissolved in 20 ml. of boiling 95% ethanol and treated with a solution of 925 mg. (0.00615 mole) of tartaric acid in 5 ml. of warm 95% ethanol. The tartaric separates in white crystals, M.P. 238239 C. dec.; yield, 0.85 g. A second crop of 0.75 g., M.P. 238-239 C. dec., is obtained from the mother liquor and combined with the first crop. Three recrystallizations from 95% ethanol give product of constant specific rotation;

M.P. 238239 C. dec.

Analysis.Calcd fOI' C20H23N02'1/2C4H6O6: C, H, 6.82, Found: C, 68.33; H, 6.71.

The tartrate, 950 mg. (0.00247 mole), is dissolved in 20 ml. of water, the solution made strongly basic with 5% aqqueous sodium hydroxide, and the oily base extracted into benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the crystalline base. Recrystallization from a mixture of benzene and hexane gives 556 mg. of product, M.P. 156158 C.,

[ 1%?....+1100 (i5 to Analysis.-Calcd for C H NO C, 77.64; H, 7.49; N, 4.53. Found: C, 77.71; H, 7.42; N, 4.63.

What is claimed is:

1. A compound of the formula Z A F x X l X R, CH2 CH2CH2N or a non-toxic salt thereof; wherein Z is the radical H, OH, OY, NH NHSO R or R ll R is lower alkyl or the radical wherein B is hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, and n is a whole number of from 0 to 3; R is hydrogen or lower alkyl; R and R" are each lower alkyl or together form "with the nitrogen atom attached thereto the radical l-piperidyl, l-pyrrolidyl, 4- morpholinyl or l-loweralkyl-4-piperazinyl; R' is lower 38 alkyl; Y is alkanoyl or from 1 to 18 carbon atoms, or the radical wherein B and n are as defined; A is hydrogen when Z is H, OH, OY, NH NHSO R or or the radical R when Z is OH or OY, or Z and A together form the radicals =NOR", =NOY or =NNH and X and X are each hydrogen, lower alkyl, lower alkenyl, halogen, trifluoromethyl, hydroxy, lower alkoxy,

mercapto, loweralkylmercapto, loweralkylsulfonyl, sulfa'moyl, loweralkylsufamoyl or diloweralkylsulfamoyl.

2. A compound of the formula or a non-toxic salt thereof; wherein Z is the radical H, OH, OY, NH NHSO R or R is lower alkyl or the radical wherein B is hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy and n is a whole number of from 0 to 3; R is hydrogen or lower alkyl, R is lower alkyl; R' is lower alkyl; Y is alkanoyl of from 1 to 18 carbon atoms, or the radical wherein B and n are as defined; A is hydrogen when Z is H, OH, OY, NH NHSO R or or the radical R' when Z is OH or OY, or Z and A together form the radicals =NOR, =NOY or =NNH and X and X are each hydrogen, lower alkyl, lower alkenyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, mercapto, lower alkylmercapto, loweralkylsulfonyl, sulfamoyl, loweralkylsufamoyl or diloweralkylsulfamoyl.

3. A compound of the formula 4. A compound of the formula CHzCHzCHaNHR or a non-toxic salt thereof; wherein R is lower alkyl; and X and X are each hydrogen, lower alkyl, lower alkenyl, halogen, trifiuoromethyLhydroxy, lower alkoxy, mercapto, loweralkylmercapto, loweralkylsulfonyl, sul-' famoyl, loweralkylsulfamoyl or diloweralkylsulfamoyl.

5. A compound of the formula CHzCHzCHzN 01120 I120 HzNHR' or a non-toxic salt thereof; wherein R is lower alkyl;

and X and X are each hydrogen, lower alkyl, lower alkenyl, halogen, trifluoromethyl, hydroxy, lower alkoxy,

mercapto, loweralkylmercapto, loweralkylsulfonyl, sulfamoyl, loweralkylsulfamoyl or diloweralkylsulfamoyl.

7. A compound of the formula or a non-toxic salt thereof; wherein Y is of from 1 to carbon atoms, or the radical wherein B is hydrogen, halogen, trifiuoromethyl, lower alkyl or lower alkoxy and n is a whole number of from to 3; R and R'are each lower alkyl or together form with the nitrogen atom attached thereto the radical '1- piperidyl, l-pyrrolidyl, 4-morpholinyl or l-loweralkyl- 4-piperazinyl; and X and X are each hydrogen, lower alkyl, lower alkenyl, halogen, trifiuoromethyl, hydroxy, lower alkoxy, mercapto, loweralkylrnercapto, loweralkylsulfonyl, sulfamoyl, loweralkylsulfamoyl or diloweralkylsulfamoyl.

Q i comoound of the formula CH2CH2QH2NHR or a non-toxic'salt thereof; wherein R is lower alkyl; Y is alkanoyl of from 1 to 18 carbon atoms, or the radical wherein B is hydrogen, halogen, trifluoromethyl, lower alkyl orlower alkoxy. and n is-a whole number of from 0-to 3; and X and X are each hydrogen, lower alkyl, loweralkenyl, halogen, trifiuoromethyl, hydroxy, lower alkoxy, mercapto, loweralkylmercapto, loweralkylsulfonyl, sulfamoyl, loweralkylsulfamoyl or diloweralkylsulfamoyl.

9. A compound of the formula or a non-toxic salt thereof; wherein R and R" are each lower alkyl or together form with the nitrogen atom attached thereto the radical l-piperidyl, l-pyrrolidyl, 4- morpholinyl or 1-loweralkyl-4-piperazinyl; R is hydrogen or lower alkyl; and X and X are each hydrogen. lower alkyl, lower alkenyl, halogen, trifiuoromethyl, hydroxy, lower alkoxy, mercapto, loweralkylmercapto, 10weralkylsulfonyl, sulfamoyl, loweralkylsulfamoyl or diloweralkyls ulfamoyl.

10. A compound of the formula 7' NOR" UHgCHzCHeNHR' or a non-toxic salt thereof; wherein R is hydrogen or lower alkyl; R is lower alkyl; and 'X and X are each hydrogen, lower alkyl, lower alkenyl, halogen, trifiuoromethyl, hydroxy, lower alkoxy, mercapto, loweralkylmercapto, loweralkylsulfonyl, sulfamoyl, loweralkylsulfamoyl or"diloweralkylsulfarnoyl.

11. A compound 'of the formula ,7; S NOY CHgCHzCHzN I RI! or-a non-toxic. salt thereof; whereinR and R" are each lower alkylror together form with the nitrogen atom attached thereto the radical l-piperidyl, l-pyrrolidyl, 4- morpholinylor 1-loweralkyl-4-piperazinyl; Y is alkanoyl of from 1 to 1-8 carbon atoms, or'the radical 7 wherein B is hydrogen, halogen, trifiuoromethyl, lower alkyl or lower alkoxy and n is a whole number of from 

1. A COMPOUND OF THE FORMULA 